Journal of Neurology (2022) 269:159–183

https://doi.org/10.1007/s00415-020-10362-z

REVIEW

Rituximab for the treatment of multiple sclerosis: a review

Clara Grazia Chisari1 · Eleonora Sgarlata1,2 · Sebastiano Arena1 · Simona Toscano1 · Maria Luca1 · Francesco Patti1 

Received: 4 August 2020 / Revised: 3 December 2020 / Accepted: 8 December 2020 / Published online: 8 January 2021
© Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
In the last decades, evidence suggesting the direct or indirect involvement of B cells on multiple sclerosis (MS) pathogenesis
has accumulated. The increased amount of data on the efficacy and safety of B-cell-depleting therapies from several studies
has suggested the addition of these drugs as treatment options to the current armamentarium of disease modifying therapies
(DMTs) for MS. Particularly, rituximab (RTX), a chimeric monoclonal antibody directed at CD20 positive B lymphocytes
resulting in cell-mediated apoptosis, has been demonstrated to reduce inflammatory activity, incidence of relapses and new
brain lesions on magnetic resonance imaging (MRI) in patients with relapsing–remitting MS (RRMS). Additional evidence
also demonstrated that patients with progressive MS (PMS) may benefit from RTX, which also showed to be well tolerated,
with acceptable safety risks and favorable cost-effectiveness profile.
Despite these encouraging results, RTX is currently approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia,
several forms of vasculitis and rheumatoid arthritis, while it can only be administered off-label for MS treatment. Between
Northern European countries exist different rules for using not licensed drug for treating MS. The Sweden MS register reports
a high rate (53.5%) of off-label RTX prescriptions in relation to other annually started DMTs to treat MS patients, while
Danish and Norwegian neurologists have to use other anti-CD20 drugs, as ocrelizumab, in most of the cases.
In this paper, we review the pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile and cost effectiveness
aspects of RTX for the treatment of MS. Particularly, with the approval of new anti-CD20 DMTs, the recent worldwide
COVID-19 emergency and the possible increased risk of infection with this class of drugs, this review sheds light on the use
of RTX as an alternative treatment option for MS management, while commenting the gaps of knowledge regarding this drug.

Keywords  Multiple sclerosis · Rituximab · Efficacy · Safety

Introduction Although T cells have been considered the major contrib-

Multiple sclerosis (MS) has been historically considered
as an autoimmune disease of the central nervous system
(CNS) mediated by ­CD4+ T cells reactive to myelin antigens
[1]. According to this model, the autoimmunity processes
directed to the CNS are induced by the imbalance between
CNS-reactive effector T cells of the helper-1 (Th1) and Th17
type and regulatory T cells (Treg) [2, 3].
Clara Grazia Chisari and Eleonora Sgarlata equally contributed to
the manuscript.
* Francesco Patti
patti@unict.it
1
Department “GF Ingrassia”, Section of Neurosciences,
University of Catania, Catania, Italy
2
Stroke Unit, Department of Medicine, Umberto I Hospital,
Siracusa, Italy
utors to the inflammatory activity in MS, growing evidences
shed light on B-cell role [4–6]. Indeed, it has been dem-
onstrated that B cells are present in MS lesions, meninges
and cerebrospinal fluid (CSF) and can contribute to disease
progression through several antibody-dependent (i.e., secret-
ing intrathecal IgG) and -independent mechanisms [7]. In
addition to their capability to produce antibodies after dif-
ferentiating into plasma cells B cells can also stimulate T
cells activity through antigen presentation [8], production of
soluble neurotoxic factors [9] and switch to memory cells,
­ D4+ T cells [10].
the latter stimulating self-proliferation of C
The findings of cerebrospinal fluid oligoclonal IgG bands
(OCBs), as well as the meningeal-based ectopic B-cell fol-
licles adjacent to areas of focal cortical demyelination,
suggest a more central role for B cells in MS [11–16]. In
particular, OCBs, one of the hallmarks of MS, are shown
to persist in the CSF in approximately 90% of patients [17].

13
Vol.:(0123456789)

160
OCBs produced by intrathecal B cells in the CSF contribute
to the inflammation and destruction of the myelin sheath [18,
19]. In vivo and in vitro models showed that IgG leads to
demyelination and axonal damage in a complement-depend-
ent manner [20]. These data are indirectly confirmed by the
efficacy of plasmapheresis and immunoadsorption in treat-
ing steroid-resistant MS relapses [21]. In addition, different
antibody targets, such as myelin basic protein (MBP), myelin
oligodendrocyte glycoprotein (MOG), neurofilament, sperm-
associated antigen 16 (SPAG16), coronin-1a, heat shock pro-
teins, etc., have been demonstrated in MS patients [22, 23].
Moreover, B cells are able to migrate to the CNS using
surface markers such as C–X–C motif receptor 3 (CXCR3),
CXCR5, and CC chemokine receptor 5 (CCR5). In the
meninges, these migrated B cells form ectopic B-cell folli-
cular-like structures [24].
B cells are also able to induce antigen-specific T-cell
expansion, memory formation and cytokine production, via
a highly effective and selective antigen presentation [25]. B
cells expressing co-stimulatory molecules, such as CD80,
CD86, and CD40, contribute to T-cell activation. Particu-
larly in MS patients, B-cell expression of CD80 and CD86
is higher than in controls [26].
Moreover, B-cell activation factor (BAFF), an important
survival factor balancing pro-inflammatory and regulatory
B-cell subtypes, is upregulated in MS lesions [27].
In addition, B cells from untreated MS patients (com-
pared to healthy controls) have been demonstrated to secrete
more pro-inflammatory interleukines-IL (such as IL-6) and
less regulatory ones (such as IL-10) [16, 28].
Finally, B cells host Epstein–Barr virus (EBV), which is
strongly related to MS in epidemiological analyses [29, 30].
In light of these findings, several B-cell-targeted thera-
pies have been developed. To date, available B-cell-deplet-
ing monoclonal antibodies target specific Fab domains of
­CD20+ or ­CD19+ B lymphocytes, selectively allowing the
depletion of the circulating B-cell population, apart from the
mature antibody-secreting plasma cells [31, 32]. CD20 is a
transmembrane, non-glycosylated phosphoprotein expressed
on the surface of cells of the human B-cell lineage from
pre-B cells to naïve and memory B cells. It is involved in the
generation of T-cell-independent antibody responses [33].
The most effective therapies employ monoclonal antibod-
ies depleting B cells through NK cell-mediated antibody-
dependent cellular cytotoxicity (ADCC), complement-
dependent cytotoxicity (CDC), and antibody-triggered
apoptosis [34, 35].
Anti-CD20 monoclonal antibodies currently in use for the
treatment of MS are Rituximab (RTX), Ocrelizumab (OCR),
Ofatumumab (OFA) and Ublituximab (UTX).
Rituximab (RTX) is a chimeric monoclonal B-cell-deplet-
ing anti-CD20 antibody and it was the first anti-CD20 drug
licensed for the treatment of B-cell lymphomas, refractory
13
Journal of Neurology (2022) 269:159–183
rheumatoid arthritis (RA) and antineutrophil cytoplasmic
antibody (ANCA)-associated vasculitis [36]. Two rand-
omized placebo-controlled phase 2 trials, the “Helping to
Evaluate Rituxan in Relapsing–Remitting Multiple Sclerosis
(HERMES)” and “A Study to Evaluate the Safety and Efficacy
of Rituximab in Adults With Primary Progressive Multiple
Sclerosis (OLYMPUS)”, have demonstrated the efficacy of
RTX for the treatment of relapsing–remitting MS (RRMS)
and primary progressive MS (PPMS), respectively [31, 37].
In the last years, several observational studies confirmed
the high efficacy, relatively benign safety/tolerance profile,
low cost and convenient administration regimen contribut-
ing to make RTX an interesting option for MS treatment,
attracting increasing attention as an escalation and first-line
therapy [38].
In this review, we discuss current evidence on pharma-
cokinetics, mechanisms of action, clinical efficacy, safety
profile and cost effectiveness of RTX for the treatment of
relapsing MS. With the approval of new anti-CD20 DMTs,
the recent worldwide COronaVIrus Disease 19 (COVID-
19) pandemic emergency and the possible increased risk
of infection with this class of drugs, this review raises con-
siderations regarding the use of RTX as a valid alterative
treatment option for MS management.
Methods
A search of the relevant literature (up to November 2020)
was conducted on MEDLINE (PubMed), PubMed Central,
EMBASE and Cochrane Library, applying the medical
subject headings (MeSH) terms “multiple sclerosis” and
“rituximab” and “efficacy” and “safety” and “cost analysis”
and “COronaVIrus Disease 19”. The Prisma flow diagram
is illustrated in Fig. 1. If publications were not available via
open or institutional access, the authors of the papers were
contacted.
From the web-based search, we selected peer-reviewed,
full-text and English language manuscripts. Randomized
controlled trials (RCTs) with their extension trials and sub-
studies, prospective studies, non-randomized clinical tri-
als, retrospective studies, post hoc analyses, meta-analyses,
reviews, and studies made from registries were included. We
excluded single case studies, pediatric studies, and non-peer-
reviewed publications. Each selected paper was preliminar-
ily examined by both the authors FP and SA (via abstract
reading), downloaded and summarized.
Pharmacokinetics
Considering that RTX was widely studied in hematological
diseases, most pharmacokinetic data do not come from stud-
ies concerning MS. Historically, apart from hematological
Journal of Neurology (2022) 269:159–183 161
Fig. 1  PRISMA diagram of the literature search
diseases, RTX was studied in other immune-mediated dis-
eases, like RA [39]. It has been demonstrated that the aver-
age half-life for standard intravenous administration of RTX
(2 × 1000 mg 2 weeks apart) is nearly 20 days, but it can vary
depending on sex, body mass index (BMI) and renal clear-
ance [40]. A smaller study in MS reproduced comparable
results [41]. It has been supposed that RXT could negatively
interfere with the activity of meningeal B-cell follicles driv-
ing the inflammatory cascade behind a closed blood brain
barrier (BBB) [42]. However, big molecules (e.g., antibodies
like RXT) do not easily overcome the BBB. This was con-
firmed by a study evaluating three RRMS patients treated
with RTX, whereby the Positron Emission Tomography
Computed Tomography (PET-CT) showed very low levels of
RTX inside the CNS [43]. Another paper reported that RXT
peak concentration was 400- to 1000-fold lower compared to
serum concentrations until 4 weeks after intravenous admin-
istration [44]. Some studies also examined the administra-
tion of RTX through lumbar puncture (1–25 mg) or intra-
ventricular catheter, demonstrating a rapid CSF clearance of
the drug, probably depending on the Fc-receptor-mediated
immunoglobulin efflux [45–47]. In a study involving 27 sec-
ondary progressive MS (SPMS) patients, intrathecal RTX
administration showed a 20-fold higher bioavailability com-
pared to intravenous infusion (2 vs 0.1% after intravenous
administration) [44, 45, 48]. The authors concluded that
the intrathecal RTX administration might be effective on
intrathecal B cells and it could be adopted to reduce systemic
doses, thus reducing risks. In accordance with these data, it
has been highlighted that a low-dose intrathecal administra-
tion of RTX led to a profound peripheral B-cell depletion
for up to 12 months, supporting the hypothesis that lower
intravenous RTX doses might be sufficient to proficiently
control peripheral B-cell levels [45, 49].
Pharmacodynamics
The RTX mechanism of action consists of binding a
specific overlapping core epitope (170ANPS173) on the
extracellular CD20 loop. The adjacent amino acids also
contribute to binding. Consequently, the bond stability
13

162
may vary [50]. RTX induces cell death through apoptosis,
ADCC, antibody-dependent cell-mediated phagocytosis,
and CDC mechanisms [50]. Compared to OCR, RTX
binds weaker to the low-affinity variant of FcƔRIIIa,
which is present in over 80% of MS patients. These
data may explain why RTX induces more CDC (and
less ADCC) [50–54] and displays a lower incidence of
infusion-related reactions (IRR) when compared to OCR
[37]. As showed in pharmacokinetics studies, the intra-
venous administration of RTX causes rapid and complete
depletion of B cells both in blood [55] and, with a lesser
degree, in the CSF [56]. The exact mechanism by which
the depletion of B and T cells contrasts the inflammatory
activity in MS patients is not fully understood. It has been
speculated that it could be linked to the indirect effects
depending on B cells, such as cytokine production (i.e.,
inflammation-driving granulocyte–macrophage colony-
stimulating factor—GM-CSF—or modulators of T-cell
activity) [57, 58]. RTX also induces apoptosis in small
subgroups of pro-inflammatory C ­ D3+ T cells expressing
CD20 [59, 60]. Moreover, another hypothesis sheds light
on Epstein–Barr virus (EBV) that, according to several
studies, may be considered implicated in MS develop-
ment [61]. With this regard, some effects of anti-CD20
drugs could be related to the clearing of the viral pool
(Fig. 2) [62].
Fig. 2  Rituximab mechanisms of action. MS multiple sclerosis, MAC membrane attack complex
13
Journal of Neurology (2022) 269:159–183
Clinical efficacy
Phase I and pivotal studies
The preliminary safety, tolerability and efficacy profiles of
RTX were initially established in a phase I open-label study
of RRMS patients receiving a double course (2 weeks apart)
of 1000 mg of RTX at baseline and after 6 months, with a
follow-up of a total of 72 weeks [41]. Main clinical out-
comes of efficacy included the proportion of patients expe-
riencing a confirmed relapse and the number of relapses per
patient during the study. MRI imaging outcomes were the
total number of new gadolinium (Gd)-enhancing T1 lesions,
of new T2 lesions and the cumulative volume of T2 brain
lesions. This study demonstrated that in active MS patients,
peripheral B-cell depletion was associated with sustained
reductions in the number of relapses (annualized relapse
rates [ARR] 0.18 on week 72 compared to 1.27 in the year
before the study), while the majority of the subjects (80.8%)
remained relapse free. Concomitantly, Gd-enhancing lesions
were completely suppressed by week 72 (from a mean num-
ber of lesions of 1.31 per patient at baseline) and the mean
number of new T2 lesions decreased over the course of the
study (from 0.92 at week 4 to 0 at week 72) [41].
In 2008, a pivotal randomized double-blind placebo-
controlled multicentre phase 2 clinical trial (HERMES)
was carried out to evaluate the effects of RTX in a cohort
Journal of Neurology (2022) 269:159–183 163
of 104 RRMS patients over 48 weeks. A total of 69 patients
were randomized to receive 1000 mg of intravenous RTX,
while 35 patients were assigned to placebo on days 1 and 15,
respectively. In the RTX group, the proportion of patients
reporting clinical relapses was significantly lower compared
to placebo at week 24 (14.5 vs. 34.3%, p = 0.02) and week 48
(20.3 vs. 40.0%, p = 0.04). Moreover, patients who received
RTX had a pronounced reduction (91%) in the cumulative
number of Gd-enhancing lesions at weeks 12, 16, 20, and
24 (p < 0.001), and these results were sustained at week 48
(p < 0.001) [31].
Phase II/III studies
RTX was also evaluated in a double-blind, placebo-con-
trolled, multicentre phase II/III clinical trial investigating
efficacy, safety and tolerability in 439 patients with PPMS
(OLYMPUS) [37]. Patients were randomized to receive two
intravenous infusions (2 weeks apart) of 1000 mg of RTX
(n = 292) or placebo (n = 147) every 24 weeks, throughout
96 weeks. This study considered, as primary efficacy out-
come measure, the time-to-confirmed disease progression,
defined as a sustained Expanded Disability Status Scale
(EDSS) increase of 1.0 point from baseline if the baseline
EDSS was between 2.0 and 5.5 points, or an EDSS increase
of 0.5 point if the baseline EDSS was > 5.5 points. MRI
outcomes included the change in the volume of T2 lesions
and in brain volume from baseline to week 96. Although
this trial failed to demonstrate any significant effect on dis-
ease progression in patients with PPMS, sub-group analyses
suggested a possible beneficial impact in younger patients
(aged ≤ 51  years) with active inflammatory lesions, as
denoted by Gd-enhancing lesions on cranial MRI. As for
the secondary endpoint, patients treated with RTX had less
increase in T2 lesion volume (p = 0.010), while the brain
volume change was similar to placebo (p = 0.62).
In a Sweden class IV evidence study evaluating the safety
and efficacy profile of RTX in a large multicentre cohort
(n = 822), a remarkably low annualized relapse ratio of 0.044
and a constant median EDSS score over the follow-up period
were observed in the RRMS population treated with a dose
of 500–1000 mg of RTX every 6–12 months [36].
Based on these promising results, in 2010, another small
MRI-blinded phase II trial for RTX was performed on 30
subjects with RRMS who had experienced a relapse within
the past 18 months despite the use of an injectable DMT,
and with at least 1 Gd-enhancing lesion on any of the 3 pre-
treatment MRI scans [63]. The trial evaluated the safety,
efficacy and tolerability of add-on RTX administered at a
regimen of four times 375 mg/m2 intravenously (i.v.) weekly.
Considering the primary endpoint concerning radiologi-
cal disease activity, 74% of post-treatment MRI scans did
not show any Gd-enhancing lesions compared with 26% at
baseline (p < 0.0001). Importantly, the combination of RTX
with standard DMTs was overall well tolerated, with few
adverse effects. Several studies were performed to compare
efficacy and safety profiles of RTX versus other DMTs.
Observational studies
The Swedish group has carried out a clinical comparison
of RTX versus fingolimod (FTY), used as exit strategy in
patients discontinuing natalizumab (NTZ) due to positive
JCV status, in a multicentre, observational, cohort study of
256 RRMS patients at three MS centers in Sweden based
upon the Swedish MS register [64]. This study demonstrated
that patients who switched to RTX displayed significantly
less MRI lesions (number of new Gd-enhancing lesions: 1%
on RTX vs. 16% on FTY), clinical relapses (2% of patients
relapsing on RTX vs 18% on FTY) and adverse events (5%
on RTX vs 21% on FTY), along with a better overall drug
survival compared with FTY, as a result of a reduced dis-
continuation rate and a better tolerability.
Efficacy and safety of RTX were also tested in an obser-
vational study from Southern Switzerland involving 453
patients, of which 82 (43 (52.4%) RRMS and 39 (47.6%)
PPMS, undergoing a RTX induction regimen first and a
maintenance regimen then [65]. Number of relapses, EDSS
worsening, MRI lesion accrual and “evidence of disease
activity” (EDA) status were the main outcomes. The most
common DMTs used before RTX were NTZ and FTY and
a comparison between therapies was performed. Com-
pared with NTZ-treated patients, those treated with RTX
showed reduced disease activity and a similar time to EDA
(HR = 1.64, 95%CI 0.46–5.85, p = 0.44), further support-
ing a comparable efficacy between these two monoclonal
antibodies. Moreover, no relapses occurred in patients who
switched from NTZ to RTX because of positive JCV serol-
ogy, as previously suggested in another study [64], highlight-
ing that RTX may represent a valid treatment option in this
context as well.
Moreover, in a recent real-world retrospective compara-
tive Swedish study in newly diagnosed RRMS patients
treated with a first line DMT, RTX showed to have a lower
discontinuation rate and a better clinical efficacy compared
to injectable DMTs and dimethyl-fumarate (DMF). In com-
parison with FTY and NTZ, relapse rates and Gd-enhancing
lesions were numerically lower but did not reach statistical
significance in all analyses [66].
Given the importance of starting treatment in RRMS
patients as early as possible to reduce disability accumula-
tion, RTX was evaluated as induction therapy in a study test-
ing if RTX followed by glatiramer acetate (GA) monother-
apy was more effective than GA alone for the treatment of
active forms of RRMS [67]. The study results indicate that
induction therapy with RTX followed by GA was superior to
13

164
placebo induction and GA monotherapy in reaching NEDA
(44.4% of participants in the R-GA arm vs 19.2% in the
P-GA arm) in patients with active MS, although the effect
appeared to be temporally limited.
Data about efficacy of RTX in MS population are sum-
marized in Table 1.
Safety and tolerability
Infusion‑related reactions (IRR)
The most common adverse events (AEs) described during
the use of RTX in MS populations were the IRRs [38, 68]. In
two randomized clinical trials, IRRs appeared in 67.1% (pla-
cebo: 23.1%) and 78.3% of patients (placebo: 40.0%) respec-
tively, after the first infusion [31, 37]. IRRs levels decreased
to those observed in placebo arms with subsequent infu-
sions [31, 37]. Two smaller studies reported 25–26% of
patients being affected by infusion reactions [68, 69]. The
vast majority of these reactions are mild-to-moderate and
include fever, rush, and chills. Other frequent IRRs include
nausea, vomiting, pruritus, angioedema, throat irritation,
bronchospasm, hypotension, rhinitis, urticaria, headache,
myalgia, dizziness, and hypertension. The IRRs typically
arise 30–120 min after initiating the first infusion and usu-
ally resolve with slow withdrawal, infusion discontinuation
or symptomatic treatment. Premedication with paracetamol,
prednisone and antihistaminic drugs may reduce the prob-
ability of infusion-related adverse effects [70, 71].
In a recent study, the incidence of IRRs was similar in
RTX compared to OCR-treated patients, suggesting that
switching between them is safe and that the mechanism
behind the IRRs may be related at least in part to B-cell
levels [72].
Allergic anaphylactic reactions are less commonly
observed. The incidence of severe hypersensitivity reactions
is < 10% in cancer patients treated with RTX [73] and they
rarely necessitate treatment discontinuation. The risk can
be reduced by pre-medication with corticosteroids, antihis-
tamines and antipyretics [71].
Susceptibility to infections
In general, treatment with RTX, especially after longer
treatment periods, is associated with an increased risk of
infections [37, 74–76]. A recent register-based study in
MS population reported that RTX treatment was associ-
ated with the highest rate of serious infections compared
with NTZ, FTY, interferon beta, and GA [77]. In rand-
omized clinical trials of RTX in PPMS, serious infections
occurred in 4.5% of RTX-treated patients and in < 1.0% in
the placebo [37], with no clear association to the number
13
Journal of Neurology (2022) 269:159–183
of infusions, which corroborates findings from large tri-
als [78]. Other studies have reported an increased risk for
different types of infections, mainly affecting respiratory
and urinary systems [79–83].
Safety data of 56 patients treated with RTX for MS
and neuromyelitis optica (NMO) did not report any signs
of infection after 6 months from the last infusion in 53
patients (94.6%); a mild infection was reported in one
patient and severe infections in two patients [82]. In par-
ticular, the infections/year per patient in this study was
lower that one demonstrated in other neurological diseases
[84].
Overall, there were similar incidences of infections in
the placebo (71.4%) and RTX group (69.7%) in the first
phase II study in MS; however, an increased incidence of
urinary tract infections and sinusitis was found in RTX arm
compared to placebo [31]. In a recent retrospective obser-
vational study of 84 relapsing MS treated with RTX, 36
infections were reported (among 53 non-infusion-related
adverse events), of which four were serious, including a case
of pneumonia with concomitant late-onset neutropenia [85].
Reactivation of tuberculosis, hepatitis and HIV have been
reported in patients treated with anti-CD20 medications.
Consequently, all patients should be screened for latent
infections before starting treatment [86, 87]. Indeed, espe-
cially in endemically affected areas or populations, the risk
of tuberculosis reactivation should be considered through
specific prescreening and active surveillance with latent
tuberculosis testing.
In patients treated with RTX for onco-hematological dis-
eases, 67–85% of surface antigen of the hepatitis B virus
(HBsAg)-positive patients not under antiviral therapy may
experience a flare of hepatitis, due to reactivation of hepatitis
B virus (HBV) in up to 25% of patients [88, 89]. Clinically,
the reactivation of latent HBV infection can range from a
subclinical increase of HBV DNA levels to elevated liver
enzymes or more serious clinical pictures of acute severe
hepatitis and liver failure, with a significant risk of death,
ranging from 4 to 60% [89]. Hence, to prevent the risk of
HBV reactivation, the U.S. Food and Drug Administration
(FDA) has approved changes to the prescribing information
of RTX and has added a new Boxed Warning information
about the risk of reactivation of HBV infection [90]. FDA
recommends to screen all patients for HBV infection before
starting treatment with RTX by measuring HBsAg and hepa-
titis B core antibody (anti-HBc) [91]. These recommenda-
tions are not largely applied in all the European countries
with some exceptions: for example, in Germany, before start-
ing RTX, hepatitis testing is mandatory.
On the other hand, there are several case reports and ret-
rospective investigations suggesting that RTX may induce
viral replication in patients with HCV infection and onco-
hematological diseases.
 Table 1  Efficacy data of RTX for the treatment of MS
Study characteristics Clinical data MRI data
Author Study design and Dosing regimen ARR​ EDSS Relapses Other CELs New T2 lesions
population enrolled and duration*

Bar-Or et al. 2008 Open label phase 1 Rituxan®: 1000 0.25 vs 0.18  / 1.27 ± 0.72 vs / 1.31 vs 0 No. of lesions
[41] RRMS mg i.v. at weeks 0.23 ± 0.51 0.92 vs 0
1–3, and at weeks
24–26
72 weeks
Hauser et al. 2008 Double-blind phase RTX: 1000 mg i.v. 0.37 vs 0.72,  / 0.30 ± 0.67 vs / 0.5 ± 2.0 vs  /
[31] 2, multicenter, at weeks 1–3 p = 0.08 0.54 ± 0.82, 5.5 ± 1.5,
Journal of Neurology (2022) 269:159–183

placebo-con- 48 weeks p = 0.04 p < 0.001

trolled- HERMES
study
104 RRMS (69
RTX, 35 placebo)
Hawker et al. 2009 Randomized, RTX: 1000 mg i.v.  / 0.33 vs 0.45,  / /  / Lesion volume
[37] multicenter every 24 weeks p = 0.34 (mm³)
double-blind, pla- (4 courses) 1.5 vs 2.2, p < 0.001
cebo-controlled- 96 weeks
OLYMPUS study
439 PPMS (292
RTX, 147 pla-
cebo)
Salzer et al. 2016 Retrospective, MabThera®: 500 0.044 (RRMS)  /  / / Total number 636  /
[79] multicenter mg or 1000 mg 0.038 (SPMS) vs 75
uncontrolled i.v. twice, 14 days 0.015 (PPMS) Percentage of
observational apart and after 6 patients with
RRMS, months CELs:26.2 vs 4.6
SPMS,PPMS 2 years
Naismith et al. MRI, blinded, add- RTX: 375 mg/m²  /  /  / / Median 1.0 vs 0  /
2010 [63] on therapy i.v. 4 times in Mean 2.81 ± 0.41
RRMS weekly intervals vs 0.33 ± 0.1
plus β-IFN s.c. p < 0.001 (88%
every other day reduction)
52 weeks
Alping et al. 2016 Prospective, RTX: 0.5 or 1 gr 0.02 vs 0.16  / Percentage of / Percentage of  /
[64] unblinded, multi- every 6 months patients with patients with
center i.v. vs FTY 0.5 relapses: 1.8 vs CELs: 0.01 vs
RRMS who mg 1 tablet a day 17.6 0.24
suspended NTZ 1.5 years
because of PML
risk

13
165


Table 1  (continued)
166

Study characteristics Clinical data MRI data

13
Author Study design and Dosing regimen ARR​ EDSS Relapses Other CELs New T2 lesions
population enrolled and duration*

Scotti et al. 2018 Retrospective, RTX: 500 mg  / Percentage of 5 vs 9, p = 0.99 Time to NEDA 2 in RRMS vs 1 in 12.5% vs 2.6%
[65] observational, (n = 7) or 1 gr patients with between RTX PMS, p = 0.99
propensity score (n = 74) on days EDSS progres- and NTZ
matched 1 and 15, at 9 sion: (HR = 1.64,
43 RRMS months and then 16.3 in RRMS 95%CI = 0.46–
39 PMS every 6 months; vs 20.5 in PMS 5.58, p = 0.44)
NTZ: 300 mg i.v.
monthly (n = 83)
36 months
Granqvist et al. Retrospective, RTX: 1000 mg i.v. / / Percentage of / Percentage of  /
2018 [66] multicenter twice, 14 days patients with patients with
494 RRMS apart and after 6 relapses CELs
months RTX: 5 RTX: 7% vs INJ
3 years INJ: 27 12.6% p < 0.01,
DMF: 11.6 vs DMF 12.8%,
FTY: 17.6 p = 0.05, vs FTY
NTZ: 20 5.9%, p = 0.46, vs
NTZ 6%, p = 0.07
Honce et al. 2019 Randomized, RTX:1000 mg i.v.  /  / Percentage of / Percentage of 0.48 vs 1.96,
[67] double-blind, pla- at days 1 and 15, patients with patients with p = 0.027
cebo-controlled followed by GA relapses: 74 vs CELs: 25.9 vs
RRMS 20 mg s.c. 50, p = 0.07 61.5%, p = 0.009
Placebo: normal
saline i.v. at days
1 and 15 followed
by GA 20 mg s.c.
4 years

RTX rituximab, ARR​ annualized relapse rate, EDSS expanded disability status scale, CEL contrast-enhanced lesion, MRI magnetic resonance imaging, INJ injectable disease modifying drugs,
β-IFN beta-interferon, DMF dimethyl-fumarate, FTY fingolimod, NTZ natalizumab, GA glatiramer acetate NEDA no evidence of disease activity, i.v. intravenously, s.c. subcutaneously, RRMS
relapsing–remitting multiple sclerosis, PMS progressive multiple sclerosis, SPMS secondary progressive multiple sclerosis
*Brand name was reported when available
Journal of Neurology (2022) 269:159–183
Journal of Neurology (2022) 269:159–183 167
Although less frequently reported, other possibly RTX-
associated infections include cytomegalovirus (CMV),
herpes simplex virus (HSV), varicella zoster virus (VZV),
and West Nile virus [76]. Particularly, CMV disease is an
uncommon adverse event in RTX-treated patients, except in
those with HIV infection or following allogenic transplant;
indeed, there are several reports showing CMV disease in
patients with hematologic malignancies treated with com-
bined chemotherapy [92]. Cases of HSV and VZV reactiva-
tion have also been reported in patients administered RTX
for lymphoma [76]. Cases of Pneumocystis jirovecii pneu-
monia has been reported among patients treated with RTX
for aggressive B-cell lymphoma as part of specific chemo-
therapy regimens including other immunosuppressant such
as cyclophosphamide [76, 93].
In the last years, the risk of progressive multifocal leu-
koencephalopathy (PML) by JCV has gained ever greater
importance in the management of several of the current MS
DMTs, in particular NTZ. PML cases have been reported
in patients with lymphoma treated with RTX; however,
the JC viral reactivation was due to the immunosuppres-
sion related to the disease [94]. Recent observational data
from over 100,000 MS patients in the FDA Adverse Event
Reporting System database have indicated that RTX-treated
patients have an increased PML risk with an adjusted odds
ratio = 3.22; 95% confidence interval (CI) =1.07–9.72 [95].
Recently, in the nationwide register-based cohort study
conducted in Sweden, one case of RTX-related PML was
described (the patient had switched from NTZ within
6 months before the diagnosis of PML). No deaths due to
infections were recorded among the patients treated for MS
[77].
The pathophysiology of RTX-associated PML remains
unclear. Data about the JCV reactivation and development
of PML in patients with congenital disorders of humoral
immunity have suggested that B lymphocytes may play a
role in the JCV immune responses [96]. However, the mech-
anisms underlying viral reactivation after RTX treatment
could also involve the changes in T-lymphocyte activity after
B-lymphocyte depletion due to the alteration of T-lympho-
cyte cytokine profiles [97]. In a review of PML cases among
RTX-treated patients referring to the 1997–2008 FDA data-
base, 52 patients with B-cell lymphoproliferative disorder, 2
patients with systemic lupus erythematosus, one patient with
RA, one patient with an idiopathic autoimmune pancytope-
nia, and one patient with immune thrombocytopenia devel-
oped PML after RTX with a median time to death after PML
diagnosis of 2.0 months and a mortality rate of 90% [94].
In MS settings, as showed in NTZ-treated patients, RTX-
associated PML is more frequently seen in immune-compro-
mised patients. A recent population-based Swedish study
reported that after two decades of stable PML incidence of
0.026/100,000 person-years, the incidence has increased to
0.11 in 2011–2013, apparently related to the use of mono-
clonal antibodies therapies [98]. Considering that all patients
treated with NTZ regardless of duration of therapy, the inci-
dence of PML exceeded one in 250 (4.22/1000 with con-
fidence intervals of 3.91–4.51/1000) [99]. The incidence
of PML was very low in the first 12 months of infusion,
though it has been observed within 8 months of drug initia-
tion [100].
The incidence of PML due to RTX treatment is estimated
to be one case per 32,000 [101]. However, even if there are
no specific recommendations to screen patients for JCV
prior to administration of RTX, it is important for clinicians
to keep in mind that RTX may be associated to PML, and it
is crucial to suspend therapy in the event of signs and symp-
toms suggestive of PML, and urgently carry out a specific
workup in order to reduce morbidity and mortality.
Laboratory test abnormalities
One of the most reported laboratory values alterations in MS
patients is hypogammaglobulinemia, especially with long-
term RTX treatment [102]. The underlying mechanism for
the development of hypogammaglobulinemia is unknown;
however, it could be hypothesized that the diminished
B-cell-secreted cytokines, such as BAFF [103] and inter-
leukin 6 [104], may determine a reduction in the formation
of plasma cells from precursors.
In an observational retrospective study on MS patients,
25 out of 822 patients (3%) had IgG levels below the lower
normal reference value (< 6.2 g/L) at some point during
treatment. There was, however, no difference in IgG lev-
els between 500 and 1000 mg RTX [36]. In another study
on NMO spectrum disorder (NMOSD) patients, 11 out
of 15 patients (73%) developed hypogammaglobulinemia
(IgG < 7 g/L) and three patients (20%) had severe hypogam-
maglobulinemia (< 4 g/L) [105]. In RA, 1.5–5.9% out of
1039 patients had hypogammaglobulinemia (IgG < 5 g/L)
[106]. None of the studies assessing the safety profile of
cumulative doses of RTX in RA demonstrated a higher
risk of hypogammaglobulinemia with increasing numbers
of RTX cycles [107, 108]. Moreover, low gamma-glob-
ulin baseline levels may be more relevant than treatment
duration/cumulative RTX doses in predicting the develop-
ment of hypogammaglobulinemia. Furthermore, sustained
hypogammaglobulinemia (≥ 4 months) was associated with
an increased risk for serious infections in open extension
studies [105, 109]. For all these reasons, the measurement
of total serum immunoglobulins before starting RTX and
at least yearly during treatment is strongly recommended.
Late-onset neutropenia (LON) is defined as an absolute
neutrophil count of < 1.5 × 10 to the power of 9/L occur-
ring > 4 weeks following the last dose and was described
as a rare complication during RTX treatment. About
13

168
5–27% of RTX-treated lymphoma patients may present
LON [110]. A similar incidence is reported in patients
with autoimmune diseases, with a higher infection rate
during the neutropenic period [111]. Recently, it has been
hypothesized that host-related factors, such as polymor-
phisms in FCGR3, may play a role in the development of
LON [111].
The incidence of LON is likely to be much lower in MS
patients. In a retrospective analysis of 385 patients treated
with RTX for NMOSD, MOG-antibody-associated disease
(MOGAD) and MS, LON was found in 10 (2.6%) patients;
in particular, 16% were affected by MOGAD, 10% were
NMOSD, and only 1.2% were MS patients [112].
Moreover, in an observational study, 1 of 90 MS
patients developed agranulocytosis 3  months after the
RTX infusion [113]. The mechanism by which RTX
induces LON/agranulocytosis is still unknown; however,
it is probably immune mediated, involving the anti-gran-
ulocyte antibody production and the neutrophil apoptosis
by the large granular lymphocyte population [111].
Malignancies
Sporadic cases of malignancies in RTX-treated MS
patients have been reported [83, 114]. In a large Swed-
ish nationwide study, no higher risk of malignancies was
found in RTX patients compared to the general population
[115]. Moreover, in MS setting, a low frequency of all
types of malignancies was reported, which did not differ
significantly from the general population (26.6 [15.2–43.3]
in RTX vs 28.9 [25.3–32.7] in the general population)
[116].
Other AEs
Studies of RTX in MS and non-MS populations have
reported several AEs involving cardiovascular system (i.e.,
angina pectoris, cardiac arrhythmias, heart failure and/or
myocardial infarction), upper and lower airways (i.e., bron-
chospasm, chest pain, dyspnoea, cough, rhinitis), gastroin-
testinal system (i.e., vomiting, abdominal pain, dysphagia,
stomatitis, constipation, dyspepsia, anorexia, reflux disease,
abdominal pain, diarrhea, gastritis, pharyngolaryngeal pain),
musculoskeletal and connective (i.e., myalgias, arthralgias,
arthritis; hypertonia, pain), nervous system (paraesthesia,
hypoesthesia, agitation, insomnia, vasodilatation, dizziness,
anxiety, fatigue, neuropsychiatric disorders), skin (i.e., rash,
itching, pruritus, alopecia) and endocrine system [31, 37,
45, 117–125].
Data about safety profile of RTX are summarized in
Table 2.
13
Journal of Neurology (2022) 269:159–183
Anti‑drug antibodies (ADAs)
In recent years, as the evidence suggesting the high clinical
efficacy of RTX have increased its off-label use in MS, sev-
eral studies explored the degree of immunogenicity and, in
particular, the possible interference of anti-drug antibodies
(ADAs) with RTX efficacy. ADAs were identified in a third
of MS patients treated with RTX, with a title higher than
that recorded in other diseases treated with the same drug.
Moreover, a lower frequency of ADAs was seen in PMS,
compared to RRMS [69]. In two randomized trials, 24.6 and
29% of RRMS patients had developed ADAs at 48 weeks
[31, 41]. In a study involving PPMS patients, 7.5% under
RTX treatment versus 3.4% under placebo were found posi-
tive for ADAs 1 year after the last infusion [37]. Recently, a
large cross-sectional real world using a more sensitive tech-
nique showed ADA in 38% of the RRMS patients and in
27% of PPMS [69].
However, the role of ADAs in treatment failure is uncer-
tain. However, such a failure could relate to the higher level
of immunological activity found in the earlier relapsing
stage of the disease. Interestingly, a negative relationship
found between the number of infusions and the frequency
of ADAs suggests that the risk of developing ADAs and
experiencing a lack of effect might diminish over time [69].
Nevertheless, outside of trials, the detection of ADAs could
be technically difficult, poorly standardized and hard to
apply in routine use.
Hence, although ADAs are present in a large propor-
tion of RTX-treated patients, the existing evidence does not
support a clinically relevant role for anti-RTX antibodies.
Indeed, several studies have demonstrated that the presence
of ADAs does not correlate with a higher incidence of infu-
sion reactions, adverse events, or lack of clinical effect [31,
37, 41]. However, larger prospective studies are needed to
confirm these data.
Vaccinations
Data from the oncology and rheumatology literature have
shown that the response to vaccination may be ineffective
in patients receiving RTX [126]. In particular, no protective
serologic responses to a single-dose influenza A vaccina-
tion were achieved in lymphoma patients within 6 months of
RTX treatment [127]. In another study evaluating the effects
of RTX on the antibody and cellular responses to Strep-
tococcus pneumonia polysaccharide vaccine and Haemo-
philus influenza type b (Hib) conjugate vaccine in patients
with immune thrombocytopenia, antibody responses were
impaired for at least 6 months after RTX treatment [128].
However, a study of patients with autoimmune blister-
ing skin diseases previously treated with RTX reported a
robust recall response to the seasonal influenza vaccination,
 Table 2  Adverse events of RTX treatment (pooled data from randomized controlled trials/registries in MS and non-MS populations)
Organ systems affected Adverse event(s) Frequency* References

Systemic Immediate-type adverse reactions Infusion- related reactions, angioedema, infusion Very common [31, 37, 38, 68–72]
reactions
Hypersensitivity Common
Late-type immune-mediated adverse reactions Serum sickness Very rare [73]
Anaphylaxis cytokine release syndrome Rare
Infections Bacterial and viral infections, bronchitis Very common [31, 37, 74–101]
Sepsis, pneumonia, febrile infection, herpes zoster, Common
fungal infections, acute bronchitis, sinusitis, hepatitis
Journal of Neurology (2022) 269:159–183

B (including reactivation)
Serious viral infection, Pneumocystis jirovecii Rare
PML Very rare
Neoplasms Worsening or reactivation of Kaposi sarcoma (in Rare [83, 114–116, 125]
Castleman’s disease)
Increased risk of cutaneous melanoma Rare
Cardiovascular Myocardial infarction, arrhythmia, atrial fibrillation, tachycardia, cardiac disorder, venous thrombotic events, Common [31, 37, 117, 118, 125]
hypertension, orthostatic hypotension, hypotension
Left ventricular failure, supraventricular tachycardia, ventricular tachycardia, angina, myocardial ischemia, Uncommon
bradycardia
Severe cardiac dysfunction, heart failure Rare, very rare
Pulmonary Bronchospasm, chest pain, dyspnoea, cough, rhinitis Common [31, 37, 45, 118–120, 125]
Asthma, bronchiolitis obliterans, lung disorder, hypoxia Uncommon
Interstitial lung disease Rare
Respiratory failure, lung infiltration, hemorrhagic alveolitis (single case reported) Very rare
Gastrointestinal or hepatic Nausea Very common [31, 117, 121, 125]
Vomiting, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, reflux disease, abdominal Common
pain, diarrhea, gastritis, pharyngolaryngeal pain, reactivation of hepatitis B
Abdominal enlargement Rare
Appendicitis, gastrointestinal perforation, acute liver failure (single case reported of hepatitis C-related cryoglo- Very rare
bulinemia)
Hematologic Neutropenia, leucopenia, thrombocytopenia Very common [36, 102–111, 125]
Anemia, pancytopenia, granulocytopenia, hypogammaglobulinemia Common
Coagulation disorders, aplastic anaemia, hemolytic anaemia, lymphadenopathy Uncommon
Transient increase in serum IgM levels Very rare
Musculoskeletal and connective Myalgias, arthralgias, arthritis, hypertonia, pain Common [118, 121, 125]
Bone fractures Very rare

13
169

170 Journal of Neurology (2022) 269:159–183

comparable to healthy controls, both at a cellular and a sero-

logical level [129].
[31, 37, 123, 125] Notably, RTX is known to target all B cells, except the

[31, 37, 123–125]

early precursor pro-B cells and long-lived plasma cells that

[118–122, 125]
do not express CD20, with little or no effect on pre-existing
References

serum antibody titers produced by long-lived plasma cells,

[120] such as antibodies against childhood vaccines, including
tetanus or meningitis [130]. Moreover, after the reduction

 Frequencies are defined as very common (≥ 1/10), common (≥ 1/100–< 1/10), uncommon (≥ 1/1000–< 1/100), rare (≥ 1/10,000–< 1/1000) and very rare (< 1/10,000)
of peripheral B-cell count typically lasting for 6–9 months,
Very common
Frequency*

Uncommon

the recovery of total B-cell numbers generally occurs after

Very rare
Very rare

Very rare
Common

Common

Common 12 months; in particular, the repopulated B-cell compart-

ment mostly includes naïve cells, while the depletion of
memory B cells (MBCs) may persist in peripheral blood
even 5 years after treatment [131].
According to these data, it is recommended to wait at
Severe bullous skin reactions, Stevens–Johnson Syndrome, toxic epidermal necrolysis (Lyell’s Syndrome)

least 6 months after RTX for vaccination, while patients

Metabolism and endocrine system Hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia

should be advised to complete any required vaccinations at

RTX rituximab, MS multiple sclerosis, PML progressive multifocal leukoencephalopathy, ANCA antineutrophil cytoplasmic antibodies

least 6 weeks prior to RTX initiation. Particularly, vaccina-

tions for hepatitis B, pneumococcus, tetanus toxoid every
Paraesthesia, hypoesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety, fatigue

10 years and for influenza annually should be undertaken for

patient considered for RTX therapy. Live-attenuated or live
vaccines are not recommended during RTX treatment and
until B-cell recovery since, currently, there are no sufficient
data on the potential risk of vaccination with this kind of
vaccines [132].
Urticaria, sweating, night sweats, other skin disorder, purpura

Pregnancy and breastfeeding
Renal failure (described in ANCA-associated vasculitis)

The European Medicines Agency (EMA) and the FDA

Dysgeusia, depression, neuropsychiatric disorders,

recommend that pregnant women should not receive RTX

infusion, unless the possible benefit outweighs the poten-
Peripheral neuropathy, facial nerve palsy

tial risk [133, 134]. Indeed, not enough data are available
about B-cell levels in human neonates following maternal
exposure to RTX. However, some infants born to mothers
Rash, itching, pruritus, alopecia

exposed to RTX during pregnancy presented transient B-cell

depletion and lymphocytopenia [135].
Two cases of MS patients with a highly disabling dis-
ease form, and treated with RTX during pregnancy, were
Adverse event(s)

reported [136]. The first patient was treated with RTX dur-
ing the third trimester, showing a clinical improvement over
several weeks, while no complications were reported in her
infant. The second patient received RTX in the early second
trimester, also showing a clinical improvement and no com-
plications. It has been suggested that RTX during pregnancy
may be safe and effective when used in an appropriate con-
text. Moreover, it has been demonstrated that RTX may be
Organ systems affected

detected only in minimal concentrations in the breast milk of

Table 2  (continued)

breastfeeding patients with MS (six samples of breast milk

Nervous system

from four lactating patients) [137]. Thus, due to the lack

of largest and longitudinal studies, the choice of resuming
RTX treatment should be carefully evaluated in breastfeed-
Renal
Skin

ing patients after risk/benefit considerations.

*

13
Journal of Neurology (2022) 269:159–183 171
COVID‑19 infection risk
Nowadays, the therapeutic management of MS patients
during COVID-19 pandemic is one of the most relevant
concerns, also raised by the possible role of white matter
lesions as a virus reservoir, as for other corona-viruses
[138].
MS patients are thought to be at higher risk than the
normal population and the question of whether to continue
or stop DMTs has been raised, in the absence of formal
guidelines and a plethora of recommendations [139].
The severe pulmonary complications of COVID-19 infec-
tion, in particular the acute respiratory distress syndrome
(ARDS), are demonstrated to be immune-mediated [140].
This is also confirmed by several data showing that immuno-
suppression (or at the least the moderate immunosuppression
induced by DMTs), may exert a protective effect against the
development of severe COVID-19 infection [141]. Indeed,
the emerging knowledge of the biology of the ARDS to the
COVID-19 and of the role of the immune mechanisms con-
tributing to the disease have suggested that viral-specific
­CD8+ T-cell responses seem to eliminate the virus, while
viral-specific antibodies could probably be able to prevent
re-infection and create long-lasting immunity [142].
Nevertheless, data about the early phase of the pan-
demic highlighted that the most important independent
risk factor associated with COVID-19 infection, aside
from having close contact with people with upper respira-
tory symptoms, was the DMT category and in particular
therapies with a B-cell depleting profile [143].
More recently, the Italian “Multiple Sclerosis and
COVID-19” (MuSC-19) study also demonstrated an
increased frequency of anti-CD20 treatments in COVID-
19-infected MS patients compared with the expected fre-
quency based on Italian data. Anti-CD20 were also associ-
ated with a more severe clinical course compared to other
DMTs [144].
Accordingly, the Society of Italian Neurologists (SIN),
the Association of British Neurologists (ABN) MS and
Neuroimmunology Advisory Group practical guidance
recommended to delay further infusions of anti-CD20
drugs, as that anti-CD20 therapies may probably increase
the risk of COVID-19 infection [145].
Another study described the lethal disease course in two
severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infected patients with hematological malignan-
cies after RTX therapy. Complete B-cell depletion and the
decrease of immunoglobulin G (IgG) level in both patients
and the persistent viremia in blood samples could be cor-
related with increased morbidity, suggesting that B-cell
function might be one important mechanism in resolving
SARS-CoV-2 infection [146].
On the other hand, a case of complete recovery from
COVID-19 has been reported in a MS patient treated with
RTX for 3 years despite having a 0% B-lymphocyte count and
not developing SARS-CoV-2 IgG antibodies. These obser-
vations shed light on possible immuno-mechanisms behind
COVID-19 infection, considering that patients with mild dis-
ease symptoms have low antibody levels, whereby weak IgG
responses have been associated with a faster virus clearance.
[147].
Moreover, it was also hypothesized that while B-cell deple-
tion may not necessarily expose people to severe SARS-CoV-
2-related issues, it could inhibit protective immunity following
infection and vaccination [148]. In fact, drug-induced B-cell
subset inhibition would not influence innate and CD8 T-cell
responses, which are central to SARS-CoV-2 elimination,
nor the hypercoagulation and innate inflammation causing
severe morbidity, but it would slow down the production of
antibodies. The protective neutralizing antibody and vaccina-
tion responses are predicted to be blunted until naïve B cells
repopulate, based on B-cell repopulation kinetics and vacci-
nation responses from published RTX (NCT00676715) and
unpublished OCR (NCT02545868) trial data [149].
Particularly referring to OCR, it has been recommended
to consider the initiation of this drug only if a high-efficacy
drug is required and the use of NTZ is contraindicated.
During OCR treatment, it has been recommended to delay
further infusions [145]. Despite these stringent recommen-
dations, published data have contradicted the assumption
that patients treated with immunosuppressive drugs could
be at risk for severe complications of COVID-19. Indeed, a
case report of an OCR-treated PPMS patient who developed
COVID-19 showed that, despite complete B-cell depletion,
the infection has been resolved in few days after hospitali-
zation, and no new symptoms occurred after 14 days [141].
A very recent study analyzed the frequency and severity of
COVID-19 in patients treated with anti-CD20 in a tertiary
hospital in Madrid, Spain, one of the most affected countries
by the COVID-19 pandemic [150]. In this study, COVID-19
infection was reported in 9 (15%) cases in the whole popula-
tion, 7 (12.9%) in patients treated with RTX, and 2 (33.3%)
in patients on OCR, with no apparent relationship with the
time of the therapy administration. All patients reporting
COVID-19 did not show serious complications and only
one of them required hospital admission. Thus, the authors
suggested that patients treated with anti-CD20 could not be
particularly at risk for severe complications of COVID-19.
Cost‑effectiveness
RTX used at a single dose of 500 or 1000 mg twice yearly
results in lower treatment costs, even in comparison to plat-
form MS therapies. However, the status of being an off-label
13

172
drug, subjected to variable insurance regulations in countries
other than Sweden, remains as a potential barrier for its use
in MS patients [151].
A study showed that in 2015 the use of RTX for the
treatment of RA at the dosage of two infusions of 1000 mg
doses totally given 2 weeks apart every 6 months, costs
about $30,000 annually [152]. Although costs may vary by
region and may change over time, the current cost for the
off-label use of RTX (1000 mg spread over 2 doses) in Italy
is approximately €1,400. In Sweden, the cost of a yearly
RTX course including two doses of 500 mg costs is about
€2,400 [152, 153].
Thus, RTX costs seem to be well below the average
wholesale acquisition costs of the standard DMTs, includ-
ing the first-line drugs, which are currently estimated to cost
approximately $70,000–$80,000 or more annually [16, 152].
An American pharmacoeconomic study demonstrated
that the off-label use of RTX is less expensive than most
of the currently available FDA-approved DMTs, confirming
the results from randomized trials and observational stud-
ies showing that RTX infusions of 1–2 g annually are cost
effective, with a Weighted Average Cost of Capital (WACC)
of $16,704 per 1000 mg [151, 154].
In addition, even if the stated price of the recently
approved OCR is within the range or less than other current
approved DMTs with an annual cost of twice-a-year infu-
sions of $65,000, it remains significantly more expensive
than RTX [155].
Finally, with a price ranging from 15 to 30% lower than
the originator molecule (MabThera®), the development of
RTX biosimilars may also significantly contribute to cost
savings for healthcare systems [156, 157].
Dosing regimens
Although the US Food and Drug Administration (FDA)
approved RTX only for use in non-Hodgkin’s lymphoma
(NHL) and RA, it is commonly used as off-label treatment
for severe MS. However, due to the absence of formal head-
to-head trials of therapy regimen comparisons for RTX in
MS, there are neither consensus nor treatment guidelines on
dosing regimens.
At the beginning, basic dosing and interval strategies
for RTX in MS have been adopted from RTX usage in
oncology and RA, giving 375 mg once weekly for 4 weeks
or two infusions of 500–1000 mg given a fortnight apart
[158]. Then, in the clinical trials RTX has been admin-
istered as 1000 mg i.v. twice 2 weeks apart in patients
with RRMS [31] and as 1000 mg i.v. twice 2 weeks apart
every 24th week in four cycles in patients with PMS [37].
Nowadays, in European countries (and for most of the
neuro-immunological diseases including MS) RTX doses
13
Journal of Neurology (2022) 269:159–183
of 500 mg are typically administered every 6–9 months.
Indeed, the currently used dosing strategy in Sweden con-
sists of one i.v. dose of 500–1000 mg RTX every 6 months
[66, 69, 159], since a similar degree of C ­ D19+ B-cell sup-
pression at 6 months after infusion has been observed with
500 and 1000 mg [60].
High-dose RTX therapy often results in B-cell depletion
for approximately 12 months [160]. However, the develop-
ment of PML in patients treated could be a fearful complica-
tion, so it remains unclear whether high doses of RTX are
safe or necessary for sustained clinical efficacy in inflam-
matory diseases [161, 162]. In 2011, an open-label study
investigated the effects of a low dose of RTX on B cells
CD19 level in RRMS patients [163]. The study design was
based on the treatment of 12 patients who were refractory
to conventional DMTs with methylprednisolone 500 mg
intravenously followed by a 100 mg infusion of RTX. The
findings suggested that a single 100 mg infusion of RTX
adequately depleted peripheral B cells for at least 6 weeks,
with ­CD19+ lymphocytes recovering at levels above the 25%
of baseline at 12 weeks (27%) and at 24 weeks (45%). Dur-
ing the follow-up, there was a reduction in the number of
clinical relapses (21 in the year prior to first infusion vs 7 in
the year following) and a fewer number of baseline cumula-
tive Gd-enhanced lesions on brain MRI (23 at baseline vs
3,2, and 0 at weeks 12, 24, and 52, respectively). Thus, the
authors raised the question whether the use of minimal doses
of RTX could maintain the clinical effects in the treatment of
RRMS through a sustained B-cell depletion [163].
Growing evidence supports the hypothesis that the pro-
gressive phase of MS might be associated with intrathecal
compartmentalization of inflammatory cells; thus, several
studies investigated the effect of intrathecal administration
of immunosuppressants as a new therapeutic approach in
MS [164]. A single case report of intrathecal use of RTX
was performed in 2014 to evaluate the central and peripheral
effects of repeated intrathecal administrations of RTX in a
patient with severe PMS [165]. The investigators demon-
strated the marked reduction of peripheral ­CD20+ B cells,
several central pro-inflammatory cytokines and markers of
neurodegeneration, with no effect on oligoclonal bands.
An open-label phase 1b study on the efficacy of intrathe-
cal administration of RTX for the treatment of PMS was also
conducted, which involved the monitoring B lymphocytes in
peripheral blood and CSF up to 1 year post-treatment [166].
This study demonstrated that the intrathecal administration
of ultra-low doses of RTX was able to completely deplete
peripheral B lymphocytes, thus confirming the potential
effects in both the CNS and systemic compartments. A
randomized placebo-controlled phase II trial of combined
IV and intrathecally administered RTX in patients with
SPMS is currently ongoing (ClinicalTrials.gov Identifier:
NCT01212094).
Journal of Neurology (2022) 269:159–183 173

It has been shown that an almost complete B-cell deple- Biosimilars

tion occurs within a fortnight of infusion, usually persisting
for 6–12 months. For this reason, treatment courses have
commonly been repeated at regular six-month intervals.
However, the initial RTX dose required to achieve B-cell
depletion and the time to B-cell repopulation may consider-
ably vary [167] with a reported prolonged B-cell depletion
lasting over 3 years following a single dose of RTX [168].
Dosing and interval strategies for RTX commonly used
in onco-hematology setting and for RA treatment have been
also applied in MS patients [158]. In randomized clinical
trials, RTX has been administered as 1000 mg intravenous
twice 2 weeks apart in RRMS [31] and 1000 mg intrave-
nous twice 2 weeks apart every 24th week in four cycles
in PPMS patients [37]. Two studies have measured blood
­CD19+ B cells to schedule the RTX re-infusion [113, 169].
It has been suggested that monitoring circulating memory
B cells ­(CD19+ and ­CD27+) could be a viable strategy to
control relapsing NMO [170], which may be similarly per-
tinent to MS, in order to schedule a personalized treatment
regimen [32]. These considerations explain why in Sweden
the most common approach consists of one intravenous dose
of 500 mg RTX every 6 months [36, 64, 66, 69, 159], since it
was demonstrated that this regimen can determine a C ­ D19+
B-cell suppression at 6 months comparable to the 1000 mg
dose one [60]. On the other side, the refill of B cells has a
significant individual variability. In a study involving 439
PPMS patients, about 40% of them had recovered peripheral
B cells 48 weeks after their last dose (in the 1000 mg intra-
venous twice 2 weeks apart regimen) [37]. In another study
26 RRMS patients had a reconstitution to a mean of 35%
of baseline counts by week 72 (48 weeks after 2 × 1000 mg
2 weeks apart), in particular with a greater amount of naïve
B cells rather than memory B cells [41], producing less pro-
inflammatory and more regulatory cytokines [58]. Dosing
regimens more frequently used in MS population are sum-
marized in Table 3.
RTX’s patent expired in Europe in February 2013 and in
the US in September 2016 [171]. Since 2015, FDA and
EMA have approved several biosimilars of RTX, such as
while other biosimilars are to date in the pipeline [172,
173].
CT-P10 (Truxima®) is the first biosimilar approved
for use in all indications reported for the originator RTX,
including follicular lymphoma (FL), diffuse large B-cell
non-Hodgkin’s lymphoma, chronic lymphocytic leukemia,
RA, granulomatosis with polyangiitis and microscopic
polyangiitis. CT-P10 shares similar physicochemical and
pharmacodynamic characteristics, comparable tolerability,
immunogenicity and safety profiles with reference RTX,
and switching to CT-P10 has no impact on safety or effi-
cacy [174].
Another bioequivalent, GP2013 (Rixathon®), has been
compared to the originator RTX in patients with a diag-
nosis of FL and active RA and has shown high similarity
from a biochemical point of view [175–177].
Since a biosimilar is not the exact copy of the origi-
nator, its efficacy and safety may significantly differ. For
these reasons, a recent study tested the equivalence of the
RTX biosimilar CT-P10 and its originator RTX used for
MS treatment in terms of efficacy, safety, and tolerability
[178]. Concerning efficacy, similar C ­ D19 + lymphocyte
depletion, relapse rate and evolution of MRI activity were
observed between the two groups of treatment. Results
suggest that CT-P10 could represent a relatively cheaper
and safe therapeutic alternative and could improve access
to a highly efficient therapy for MS in low- or middle-
income countries. Recently, a prospective study demon-
strated the equivalence of the RTX biosimilar Truxima®
compared to its originator MabThera® in terms of effi-
cacy, safety, and tolerability in a MS population [178].

Table 3  Different treatment Dosing regimen Schedule Interval MS population References

dosing regimens used in MS
population 375 mg/m2 i.v Once weekly Every 4 weeks RRMS [49, 115]
500 mg i.v Once weekly 2 weeks apart RRMS [115]
1000 mg i.v Once weekly 2 weeks apart RRMS [6]
1000 mg i.v Once weekly 2 weeks apart every 6 months PMS [9]
500 or 1000 mg i.v Once Every 6 months RRMS [52, 54, 65, 116]
100 mg e.v. + 500 mg Once Every 6 months RRMS [120]
methylprednisolone
10 mg IT Once 2 months apart RRMS [121]
25 mg IT Once weekly Every week for 3 weeks PMS [122]

MS multiple sclerosis, i.v. intravenously, IT intrathecal, RRMS relapsing–remitting multiple sclerosis, PMS
progressive multiple sclerosis

13

174
Clinical use in other neurological disorders
RTX has been approved for the treatment of B-cell lym-
phomas (i.e., non-Hodgkin’s lymphoma, chronic lymphatic
leukemia) in 1997. Nowadays, RTX is being deployed for
a multitude of chronic inflammatory diseases apart from
MS, representing an attractive alternative to conventional
immunomodulatory medications because of growing evi-
dence of its efficacy and tolerability.
A recent review has summarized indications and evi-
dence for RTX use in neurological disorders depending on
the type and course of the disease [179].
RTX is usually adopted as a second-line acute therapy
in anti-NMDAR encephalitis [180] and in other autoim-
mune encephalitis [181] to maximise neurological recov-
ery. The most commonly used dosing regimen is 375 mg/
m 2 weekly for four doses. Favorable outcomes as acute
therapy have also been reported in small case series of
patients with diagnosis of primary angiitis of the CNS
[182].
Use of RTX in NMOSD is supported by numerous
studies demonstrating consistent reductions in ARR [183,
184]. No consensus exists about the exact efficient dose.
Usually, dosing regimen of 375 mg/m 2 weekly for four
cycles is adopted, but in small series of patients, NMOSD
doses as low as 100 mg weekly for 3–4 weeks have been
successfully used [185, 186].
Two randomized controlled trials have shown non-infe-
riority of RTX to cyclophosphamide in inducing remission
in patients with ANCA-associated vasculitis [187]. In par-
ticular, RTX in association with steroids is recommended
by the National Institute for Health and Care Excellence
(NICE) as an option for inducing remission of severe dis-
ease when cyclophosphamide has failed or is contraindi-
cated [188].
The treatment of immune-mediated peripheral neuropa-
thies with RTX showed modest benefits; however, there
may be circumstances in which RTX could be helpful, as
in patients with diagnosis of chronic inflammatory demy-
elinating polyradiculoneuropathy (CIDP) with an inad-
equate response to conventional therapy (corticosteroids,
intravenous immunoglobulin and plasma exchange) [181].
Finally, evidences of benefits with RTX use in patients
with refractory myasthenia gravis have been showed in
some retrospective case series, with much greater efficacy
in muscle-specific tyrosine kinase (MuSK)-associated than
acetylcholine receptor (AChR)-associated forms [189,
190].
13
Journal of Neurology (2022) 269:159–183
Discussion
An increasing body of evidence supports the high efficacy
and the low drug discontinuation rate of B-cell-depleting
anti-CD20-antibody RTX for the treatment of MS. Long-
term observation of RTX therapy in RA and in NMOSD
suggests that RTX is highly effective, safe and well toler-
ated [38, 41, 70, 81, 85]. Two large randomized clinical
trials and results from large real-world studies have con-
firmed its safety and efficacy in both RRMS and PMS [31,
37]. Furthermore, the evidence from long-term use of RTX
in other clinical conditions, such as RA, has supported its
favorable safety profile. However, it should be noted that
careful monitoring is needed, in particular considering the
infection risk. For this reason, it is recommended to meas-
ure total serum immunoglobulins before starting RTX and
during the follow-up to carry out specific vaccination at
least 6 weeks before starting RTX treatment.
In addition to the efficacy and safety data, the off-label
use of RTX is less expensive than most of the currently
available FDA-approved DMTs, confirming the results
from randomized trials and observational studies show-
ing that RTX infusions of 1–2 g annually are cost-effective
[151, 154]. However, although the annual cost of RTX is
lower than that of most MS drugs, its access is not uni-
versal because its cost remains high for some patients and
healthcare services. In that respect, the introduction of
cheaper biosimilars may further reduce costs and also
represents a highly efficient therapeutic option for MS in
low- or middle-income countries. Moreover, it is unknown
whether the introduction of new anti-CD20 monoclonal
antibodies, particularly those SC administered such as ofa-
tumumab, could also impact the price competition.
The encouraging results emerging from the trials and
observational studies have raised the question if RTX
may represent an acceptable and valid alternative to
OCR. This was also highlighted by the significant dis-
parity in cost between these two anti-CD20 drugs, with
RTX being markedly less expensive. Notably, RTX use
for MS is variably covered depending on the health system
in the European countries and according to the insurance
companies in USA. Nevertheless, it should be considered
that RTX has a more pronounced immunogenicity with a
higher production of ADAs compared to OCR, since the
unique molecular structure of OCR allows eliminating B
cells though a more direct path. Thus, in the absence of
head-to-head trials, the choice of RTX or OCR should be
made carefully on the basis of efficacy and safety issues.
A further knowledge gap is represented by the use
of RTX for the treatment of PPMS; indeed, even if data
showed that younger PPMS patients, particularly those
with inflammatory lesions, may benefit from RTX, the
Journal of Neurology (2022) 269:159–183 175
effectiveness of RTX in PPMS needs to be further explored
also taking into account specific clinical variables, such
as age, disease duration, comorbidities and evidence of
inflammatory activity defined by clinical relapses, progres-
sion rate and MRI data [37].
Another open issue is the lack of no formal dose-finding
trials of different RTX therapy regimens. Thus, further stud-
ies are needed to optimize dosing regimen, to identify the
administration interval, possibly individualized by adjust-
ment to immunological parameters and disease activity.
Moreover, in the light of the higher incidence of infections
reported in the trials, future researches may investigate if
a reduced dosing schedule may be able to reduce the risk
of infections, preserving the efficacy and also the favorable
safety profile [31, 37]. In our MS center of the University
Hospital of Catania, MS and NMO patients are treated with
1000 mg i.v. twice 2 weeks apart and the RTX re-treatment
is usually scheduled based on the refill of the ­CD20+ and
­CD19+ lymphocytes (over 1%). However, the B-cell repopu-
lation may individually vary. Hence, dose-finding studies
should be carried out to identify  “early re-populators” at
risk of disease relapse in order to retreat them before disease
progression and avoid the overtreatment of patients with sus-
tained B-cell depletion over time [167].
To date, a major concern during the COVID-19 pan-
demic has been represented by the use of immunosuppres-
sive therapies for MS treatment. This was particularly true
for Italy, as it was the first European country to face the
COVID-19 pandemic. Several data have shown encouraging
results, suggesting that immunosuppression, or at the least
the moderate immunosuppression induced by DMTs, may
have a protective effect against the development of severe
COVID-19 infection [141].
This is not surprising, as ARDS are demonstrated to be
immune mediated [140]. Besides, evidences on the immu-
nopathogenesis of ARDS due to the COVID-19 infection
have suggested that viral-specific C ­ D8+ T-cell responses are
involved in the virus clearance [142]. Notably, most MS-
related DMTs, probably except alemtuzumab, do not seem
to target the innate immune system, whereas only few of
them have any significant long-term effect on ­CD8+ T-cell
counts. More importantly, MS DMTs in general do not usu-
ally target the immature B-cell development, thus allow-
ing antibody production preventing (re)infection, as well as
response to vaccines. In the light of these findings, numer-
ous trials with immunosuppressive therapies, such as FTY
(NCT04280588), Tocilizumab (NCT04331795), Anakinra
(NCT04341584) and Emapalumab (NCT04324021) are cur-
rently being tested as treatments for COVID-19-associated
ARDS [191].
However, the recent Italian report of higher risk of
COVID infection in MS patients treated with anti-CD20
drugs has risen some concerns about the use of these class of
drugs [144]. In this study, no association between time to last
infusion of OCR and COVID-19 risk was found, supporting
the hypothesis that the immunological effects of these drugs
may last longer than 6 months. Similar to the NTZ extended-
dose strategy for reducing PML risk, this may suggest that
different RTX schedules, reducing the frequency of dosing,
or adjusting it according to the monitoring of B-cell refill,
may maintain efficacy while limiting the risk of infection.
Conclusion
Despite the status of being an off-label drug, and therefore
being subjected to variable regulations in countries other
than Italy, RTX is a valid treatment option for MS patients
considering the growing evidence about the high efficacy
and the safety profile. In this time of pandemic crisis, the
recent concern raised by the recent findings showed the
higher risk of COVID-19 infection in patients treated with
anti-CD20 drugs should not be ignored, especially for naïve
patients, during treatment-decision making. This new clini-
cal insight needs to be confirmed in other autoimmune dis-
eases. The analysis of the increasing amount of real-world
data being collected in several registries may shed new light
on the pathophysiology of the COVID-19 infection and con-
firm or reject the hypothesis regarding the higher suscepti-
bility to develop severe COVID-19 of MS patients treated
with B-cell depleting therapies.
Compliance with ethical standards 
Conflicts of interest  Clara Grazia Chisari received grant for congress
participation from Almiral, Biogen, Merck Serono, Novartis, Roche,
Sanofi and TEVA. Eleonora Sgarlata declares no conflict of interest.
Sebastiano Arena declares no conflict of interest. Simona Toscano de-
clares no conflict of interest. Maria Luca declares no conflict of inter-
est. Francesco Patti has received honoraria for speaking activities by
Bayer Schering, Biogen, Merck Serono, Novartis and Sanofi Aventis;
he also served as advisory board member the following companies:
Bayer Schering, Biogen Idec, Merck Serono, Novartis; he was also
funded by Pfizer and FISM for epidemiological studies; finally he re-
ceived grant for congress participation from Bayer Schering, Biogen
Idec, Merck Serono, Novartis, Roche, Sanofi Aventis and TEVA.
References
1. Segal BM (2019) The diversity of Encephalitogenic CD4+ T
cells in multiple sclerosis and its animal models. J Clin Med
8(1):120. https​://doi.org/10.3390/jcm80​10120​
2. Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of
multiple sclerosis. Nat Rev Immunol 15(9):545–558. https​://doi.
org/10.1038/nri38​71
3. Garg N, Smith TW (2015) An update on immunopathogenesis,
diagnosis, and treatment of multiple sclerosis. Brain Behav
5(9):e00362. https​://doi.org/10.1002/brb3.362
13

176
4. Wekerle H (2017) B cells in multiple sclerosis. Autoimmunity
50(1):57–60. https​://doi.org/10.1080/08916​934.2017.12819​14
5. Krumbholz M, Derfuss T, Hohlfeld R, Meinl E (2012) B cells
and antibodies in multiple sclerosis pathogenesis and therapy.
Nat Rev Neurol 8(11):613–623. https​://doi.org/10.1038/nrneu​
rol.2012.203
6. Li R, Patterson KR, Bar-Or A (2018) Reassessing B cell con-
tributions in multiple sclerosis. Nat Immunol 19(7):696–707.
https​://doi.org/10.1038/s4159​0-018-0135-x
7. Wanleenuwat P, Iwanowski P (2019) Role of B cells and
antibodies in multiple sclerosis. Mult Scler Relat Disord
36:101416. https​://doi.org/10.1016/j.msard​.2019.10141​6
8. Lisak RP, Benjamins JA, Nedelkoska L, Barger JL, Ragheb
S, Fan B, Ouamara N, Johnson TA, Rajasekharan S, Bar-Or
A (2012) Secretory products of multiple sclerosis B cells are
cytotoxic to oligodendroglia in vitro. J Neuroimmunol 246(1–
2):85–95. https​://doi.org/10.1016/j.jneur​oim.2012.02.015
9. Lassmann H (2018) Pathogenic Mechanisms Associated With
Different Clinical Courses of Multiple Sclerosis. Front Immu-
nol 9:3116. https​://doi.org/10.3389/fimmu​.2018.03116​
10. Jelcic I, Al Nimer F, Wang J, Lentsch V, Planas R, Jelcic I,
Madjovski A, Ruhrmann S, Faigle W, Frauenknecht K, Pinilla
C, Santos R, Hammer C, Ortiz Y, Opitz L, Gronlund H, Rogler
G, Boyman O, Reynolds R, Lutterotti A, Khademi M, Ols-
son T, Piehl F, Sospedra M, Martin R (2018) Memory B cells
activate brain-homing autoreactive CD4(+) T cells in mul-
tiple sclerosis. Cell 175(1):85–100. https​://doi.org/10.1016/j.
cell.2018.08.011
11. Lovato L, Willis SN, Rodig SJ, Caron T, Almendinger SE, How-
ell OW, Reynolds R, O’Connor KC, Hafler DA (2011) Related
B cell clones populate the meninges and parenchyma of patients
with multiple sclerosis. Brain 134(Pt 2):534–541. https​://doi.
org/10.1093/brain​/awq35​0
12. Baranzini SE, Jeong MC, Butunoi C, Murray RS, Bernard CC,
Oksenberg JR (1999) B cell repertoire diversity and clonal
expansion in multiple sclerosis brain lesions. J Immunol
163(9):5133–5144
13. Owens GP, Ritchie AM, Burgoon MP, Williamson RA, Corboy
JR, Gilden DH (2003) Single-cell repertoire analysis demon-
strates that clonal expansion is a prominent feature of the B cell
response in multiple sclerosis cerebrospinal fluid. J Immunol
171(5):2725–2733. https:​ //doi.org/10.4049/jimmun​ ol.171.5.2725
14. Qin Y, Duquette P, Zhang Y, Talbot P, Poole R, Antel J (1998)
Clonal expansion and somatic hypermutation of V(H) genes of B
cells from cerebrospinal fluid in multiple sclerosis. J Clin Inves-
tig 102(5):1045–1050. https​://doi.org/10.1172/JCI35​68
15. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo
M, Reynolds R, Aloisi F (2007) Meningeal B-cell follicles in
secondary progressive multiple sclerosis associate with early
onset of disease and severe cortical pathology. Brain 130(Pt
4):1089–1104. https​://doi.org/10.1093/brain​/awm03​8
16. Greenfield AL, Hauser SL (2018) B-cell therapy for multiple
sclerosis: entering an era. Ann Neurol 83(1):13–26. https​://doi.
org/10.1002/ana.25119​
17. Disanto G, Morahan JM, Barnett MH, Giovannoni G, Ramago-
palan SV (2012) The evidence for a role of B cells in multiple
sclerosis. Neurology 78(11):823–832. https​://doi.org/10.1212/
WNL.0b013​e3182​49f6f​0
18. Obermeier B, Lovato L, Mentele R, Bruck W, Forne I, Imhof
A, Lottspeich F, Turk KW, Willis SN, Wekerle H, Hohlfeld R,
Hafler DA, O’Connor KC, Dornmair K (2011) Related B cell
clones that populate the CSF and CNS of patients with multiple
sclerosis produce CSF immunoglobulin. J Neuroimmunol 233(1–
2):245–248. https​://doi.org/10.1016/j.jneur​oim.2011.01.010
19. Bankoti J, Apeltsin L, Hauser SL, Allen S, Albertolle ME, Wit-
kowska HE, von Budingen HC (2014) In multiple sclerosis,
13
Journal of Neurology (2022) 269:159–183
oligoclonal bands connect to peripheral B-cell responses. Ann
Neurol 75(2):266–276. https​://doi.org/10.1002/ana.24088​
20. Elliott C, Lindner M, Arthur A, Brennan K, Jarius S, Hussey
J, Chan A, Stroet A, Olsson T, Willison H, Barnett SC, Meinl
E, Linington C (2012) Functional identification of pathogenic
autoantibody responses in patients with multiple sclerosis. Brain
135(Pt 6):1819–1833. https​://doi.org/10.1093/brain​/aws10​5
21. Keegan M, Konig F, McClelland R, Bruck W, Morales Y, Bitsch
A, Panitch H, Lassmann H, Weinshenker B, Rodriguez M, Parisi
J, Lucchinetti CF (2005) Relation between humoral pathological
changes in multiple sclerosis and response to therapeutic plasma
exchange. Lancet 366(9485):579–582. https​://doi.org/10.1016/
S0140​-6736(05)67102​-4
22. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I,
Dilitz E, Deisenhammer F, Reindl M (2003) Antimyelin antibod-
ies as a predictor of clinically definite multiple sclerosis after a
first demyelinating event. N Engl J Med 349(2):139–145. https​
://doi.org/10.1056/NEJMo​a0223​28
23. Rouwette M, Somers K, Govarts C, De Deyn PP, Hupperts R,
Van Wijmeersch B, De Jong BA, Verbeek MM, Van Pesch V,
Sindic C, Villar LM, Alvarez-Cermeno JC, Stinissen P, Somers V
(2012) Novel cerebrospinal fluid and serum autoantibody targets
for clinically isolated syndrome. J Neurochem 123(4):568–577.
https​://doi.org/10.1111/jnc.12005​
24. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F
(2004) Detection of ectopic B-cell follicles with germinal cent-
ers in the meninges of patients with secondary progressive
multiple sclerosis. Brain Pathol 14(2):164–174. https​://doi.
org/10.1111/j.1750-3639.2004.tb000​49.x
25. Crawford A, Macleod M, Schumacher T, Corlett L, Gray D
(2006) Primary T cell expansion and differentiation in  vivo
requires antigen presentation by B cells. J Immunol 176(6):3498–
3506. https​://doi.org/10.4049/jimmu​nol.176.6.3498
26. Aung LL, Balashov KE (2015) Decreased Dicer expression is
linked to increased expression of co-stimulatory molecule CD80
on B cells in multiple sclerosis. Mult Scler 21(9):1131–1138.
https​://doi.org/10.1177/13524​58514​56092​3
27. Krumbholz M, Meinl E (2014) B cells in MS and NMO: patho-
genesis and therapy. Semin Immunopathol 36(3):339–350. https​
://doi.org/10.1007/s0028​1-014-0424-x
28. Ireland SJ, Guzman AA, O’Brien DE, Hughes S, Greenberg
B, Flores A, Graves D, Remington G, Frohman EM, Davis LS,
Monson NL (2014) The effect of glatiramer acetate therapy on
functional properties of B cells from patients with relapsing-
remitting multiple sclerosis. JAMA Neurol 71(11):1421–1428.
https​://doi.org/10.1001/jaman​eurol​.2014.1472
29. Lossius A, Johansen JN, Torkildsen O, Vartdal F, Holmoy T
(2012) Epstein-Barr virus in systemic lupus erythematosus, rheu-
matoid arthritis and multiple sclerosis-association and causation.
Viruses 4(12):3701–3730. https​://doi.org/10.3390/v4123​701
30. Endriz J, Ho PP, Steinman L (2017) Time correlation between
mononucleosis and initial symptoms of MS. Neurol Neuroimmu-
nol Neuroinflamm 4(3):e308. https:​ //doi.org/10.1212/NXI.00000​
00000​00030​8
31. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ,
Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A,
Smith CH, HERMES Trial Group (2008) B-cell depletion with
rituximab in relapsing-remitting multiple sclerosis. N Engl J Med
358(7):676–688. https​://doi.org/10.1056/NEJMo​a0706​383
32. Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K (2017)
Memory B cells are major targets for effective immunotherapy
in relapsing multiple sclerosis. EBioMedicine 16:41–50. https​://
doi.org/10.1016/j.ebiom​.2017.01.042
33. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ (2005) The biol-
ogy of CD20 and its potential as a target for mAb therapy. Curr
Dir Autoimmun 8:140–174. https​://doi.org/10.1159/00008​2102
Journal of Neurology (2022) 269:159–183 177
34. Lehmann-Horn K, Kinzel S, Weber MS (2017) Deciphering the
role of B cells in multiple sclerosis-towards specific targeting
of pathogenic function. Int J Mol Sci 18(10):2048. https​://doi.
org/10.3390/ijms1​81020​48
35. Ontaneda D, Hyland M, Cohen JA (2012) Multiple sclerosis:
new insights in pathogenesis and novel therapeutics. Annu Rev
Med 63:389–404. https​://doi.org/10.1146/annur​ev-med-04291​
0-13583​3
36. Salzer J, Svenningsson R, Alping P, Novakova L, Bjorck A,
Fink K, Islam-Jakobsson P, Malmestrom C, Axelsson M, Vag-
berg M, Sundstrom P, Lycke J, Piehl F, Svenningsson A (2016)
Rituximab in multiple sclerosis: a retrospective observational
study on safety and efficacy. Neurology 87(20):2074–2081.
https​://doi.org/10.1212/WNL.00000​00000​00333​1
37. Hawker K, O’Connor P, Freedman MS, Calabresi PA, Antel J,
Simon J, Hauser S, Waubant E, Vollmer T, Panitch H, Zhang
J, Chin P, Smith CH, OLYMPUS trial group (2009) Rituximab
in patients with primary progressive multiple sclerosis: results
of a randomized double-blind placebo-controlled multicenter
trial. Ann Neurol 66(4):460–471. https​: //doi.org/10.1002/
ana.21867​
38. D’Amico E, Zanghi A, Chisari CG, Fermo SL, Toscano S, Arena
S, Patti F, Zappia M (2019) Effectiveness and safety of Rituxi-
mab in demyelinating diseases spectrum: an Italian experience.
Mult Scler Relat Disord 27:324–326. https​://doi.org/10.1016/j.
msard​.2018.09.041
39. Ternant D, Bejan-Angoulvant T, Passot C, Mulleman D, Paintaud
G (2015) Clinical pharmacokinetics and pharmacodynamics of
monoclonal antibodies approved to treat rheumatoid arthritis.
Clin Pharmacokinet 54(11):1107–1123. https​://doi.org/10.1007/
s4026​2-015-0296-9
40. Ng CM, Bruno R, Combs D, Davies B (2005) Population phar-
macokinetics of rituximab (anti-CD20 monoclonal antibody) in
rheumatoid arthritis patients during a phase II clinical trial. J Clin
Pharmacol 45(7):792–801. https​://doi.org/10.1177/00912​70005​
27707​5
41. Bar-Or A, Calabresi PA, Arnold D, Markowitz C, Shafer S,
Kasper LH, Waubant E, Gazda S, Fox RJ, Panzara M, Sarkar N,
Agarwal S, Smith CH (2008) Rituximab in relapsing-remitting
multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neu-
rol 63(3):395–400. https​://doi.org/10.1002/ana.21363​
42. Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic
S, Rocca MA (2018) Multiple sclerosis. Nat Rev Dis Primers
4(1):43. https​://doi.org/10.1038/s4157​2-018-0041-4
43. Hagens MH, Killestein J, Yaqub MM, van Dongen GA, Lam-
mertsma AA, Barkhof F, van Berckel BN (2018) Cerebral ritux-
imab uptake in multiple sclerosis: a (89)Zr-immunoPET pilot
study. Mult Scler 24(4):543–545. https​://doi.org/10.1177/13524​
58517​70450​7
44. Petereit HF, Rubbert-Roth A (2009) Rituximab levels in cerebro-
spinal fluid of patients with neurological autoimmune disorders.
Mult Scler 15(2):189–192. https​://doi.org/10.1177/13524​58508​
09826​8
45. Komori M, Lin YC, Cortese I, Blake A, Ohayon J, Cherup J,
Maric D, Kosa P, Wu T, Bielekova B (2016) Insufficient dis-
ease inhibition by intrathecal rituximab in progressive multiple
sclerosis. Ann Clin Transl Neurol 3(3):166–179. https​://doi.
org/10.1002/acn3.293
46. Rubenstein JL, Fridlyand J, Abrey L, Shen A, Karch J, Wang E,
Issa S, Damon L, Prados M, McDermott M, O’Brien J, Haqq C,
Shuman M (2007) Phase I study of intraventricular administra-
tion of rituximab in patients with recurrent CNS and intraocu-
lar lymphoma. J Clin Oncol 25(11):1350–1356. https​://doi.
org/10.1200/JCO.2006.09.7311
47. Schlachetzki F, Zhu C, Pardridge WM (2002) Expres-
sion of the neonatal Fc receptor (FcRn) at the blood-brain
barrier. J Neurochem 81(1):203–206. https​://doi.org/10.104
6/j.1471-4159.2002.00840​.x
48. Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M,
Damon L, Ignoffo R, Aldape K, Shen A, Lee D, Grillo-Lopez A,
Shuman MA (2003) Rituximab therapy for CNS lymphomas: tar-
geting the leptomeningeal compartment. Blood 101(2):466–468.
https​://doi.org/10.1182/blood​-2002-06-1636
49. Topping J, Dobson R, Lapin S, Maslyanskiy A, Kropshofer H,
Leppert D, Giovannoni G, Evdoshenko E (2016) The effects of
intrathecal rituximab on biomarkers in multiple sclerosis. Mult
Scler Relat Disord 6:49–53. https​://doi.org/10.1016/j.msard​
.2016.01.001
50. Klein C, Lammens A, Schafer W, Georges G, Schwaiger M,
Mossner E, Hopfner KP, Umana P, Niederfellner G (2013)
Epitope interactions of monoclonal antibodies targeting CD20
and their relationship to functional properties. MAbs 5(1):22–33.
https​://doi.org/10.4161/mabs.22771​
51. Morschhauser F, Marlton P, Vitolo U, Linden O, Seymour JF,
Crump M, Coiffier B, Foa R, Wassner E, Burger HU, Brennan B,
Mendila M (2010) Results of a phase I/II study of ocrelizumab,
a fully humanized anti-CD20 mAb, in patients with relapsed/
refractory follicular lymphoma. Ann Oncol 21(9):1870–1876.
https​://doi.org/10.1093/annon​c/mdq02​7
52. Pawluczkowycz AW, Beurskens FJ, Beum PV, Lindorfer MA,
van de Winkel JG, Parren PW, Taylor RP (2009) Binding of
submaximal C1q promotes complement-dependent cytotoxicity
(CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab
(OFA) or rituximab (RTX): considerably higher levels of CDC
are induced by OFA than by RTX. J Immunol 183(1):749–758.
https​://doi.org/10.4049/jimmu​nol.09006​32
53. Robak T, Robak E (2011) New anti-CD20 monoclonal antibod-
ies for the treatment of B-cell lymphoid malignancies. BioD-
rugs 25(1):13–25. https​://doi.org/10.2165/11539​590-00000​
0000-00000​
54. Maloney DG (2007) Follicular NHL: from antibodies and vac-
cines to graft-versus-lymphoma effects. Hematology Am Soc
Hematol Educ Program 2007:226–232. https​://doi.org/10.1182/
ashed​ucati​on-2007.1.226
55. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, White CA, Liles TM,
Royston I, Varns C, Rosenberg J, Levy R (1997) IDEC-C2B8:
results of a phase I multiple-dose trial in patients with relapsed
non-Hodgkin’s lymphoma. J Clin Oncol 15(10):3266–3274. https​
://doi.org/10.1200/JCO.1997.15.10.3266
56. Piccio L, Naismith RT, Trinkaus K, Klein RS, Parks BJ, Lyons
JA, Cross AH (2010) Changes in B- and T-lymphocyte and
chemokine levels with rituximab treatment in multiple sclerosis.
Arch Neurol 67(6):707–714. https​://doi.org/10.1001/archn​eurol​
.2010.99
57. Bar-Or A, Fawaz L, Fan B, Darlington PJ, Rieger A, Ghorayeb
C, Calabresi PA, Waubant E, Hauser SL, Zhang J, Smith CH
(2010) Abnormal B-cell cytokine responses a trigger of T-cell-
mediated disease in MS? Ann Neurol 67(4):452–461. https:​ //doi.
org/10.1002/ana.21939​
58. Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, Moore
CS, Michel L, Althekair F, Rajasekharan S, Gommerman JL, Prat
A, Fillatreau S, Bar-Or A, Canadian BciMST (2015) Proinflam-
matory GM-CSF-producing B cells in multiple sclerosis and B
cell depletion therapy. Sci Transl Med 7(310):310ra166. https​://
doi.org/10.1126/scitr​anslm​ed.aab41​76
59. Graves J, Vinayagasundaram U, Mowry EM, Matthews IR,
Marino JA, Cheng J, Waubant E (2014) Effects of rituximab on
lymphocytes in multiple sclerosis and neuromyelitis optica. Mult
Scler Relat Disord 3(2):244–252. https:​ //doi.org/10.1016/j.msard​
.2013.10.003
60. Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A,
Hauser SL, Baranzini SE, Leppert D, von Budingen HC (2014)
13

178
Rituximab efficiently depletes increased CD20-expressing T cells
in multiple sclerosis patients. J Immunol 193(2):580–586. https​
://doi.org/10.4049/jimmu​nol.14001​18
61. Olsson T, Barcellos LF, Alfredsson L (2017) Interactions
between genetic, lifestyle and environmental risk factors for
multiple sclerosis. Nat Rev Neurol 13(1):25–36. https​://doi.
org/10.1038/nrneu​rol.2016.187
62. Guan Y, Jakimovski D, Ramanathan M, Weinstock-Guttman B,
Zivadinov R (2019) The role of Epstein-Barr virus in multiple
sclerosis: from molecular pathophysiology to in vivo imaging.
Neural Regen Res 14(3):373–386. https​://doi.org/10.4103/1673-
5374.24546​2
63. Naismith RT, Piccio L, Lyons JA, Lauber J, Tutlam NT, Parks
BJ, Trinkaus K, Song SK, Cross AH (2010) Rituximab add-
on therapy for breakthrough relapsing multiple sclerosis: a
52-week phase II trial. Neurology 74(23):1860–1867. https​://
doi.org/10.1212/WNL.0b013​e3181​e2437​3
64. Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer
J, Bjorck A, Axelsson M, Malmestrom C, Fink K, Lycke J,
Svenningsson A, Piehl F (2016) Rituximab versus fingolimod
after natalizumab in multiple sclerosis patients. Ann Neurol
79(6):950–958. https​://doi.org/10.1002/ana.24651​
65. Scotti B, Disanto G, Sacco R, Guigli M, Zecca C, Gobbi C (2018)
Effectiveness and safety of Rituximab in multiple sclerosis: an
observational study from Southern Switzerland. PLoS ONE
13(5):e0197415. https​://doi.org/10.1371/journ​al.pone.01974​15
66. Granqvist M, Boremalm M, Poorghobad A, Svenningsson A,
Salzer J, Frisell T, Piehl F (2018) Comparative effectiveness of
rituximab and other initial treatment choices for multiple sclero-
sis. JAMA Neurol 75(3):320–327. https:​ //doi.org/10.1001/jaman​
eurol​.2017.4011
67. Honce JM, Nair KV, Sillau S, Valdez B, Miravalle A, Alva-
rez E, Schreiner T, Corboy JR, Vollmer TL (2019) Rituximab
vs placebo induction prior to glatiramer acetate monotherapy
in multiple sclerosis. Neurology 92(7):e723–e732. https​://doi.
org/10.1212/WNL.00000​00000​00691​6
68. Brown BA, Torabi M (2011) Incidence of infusion-associated
reactions with rituximab for treating multiple sclerosis: a ret-
rospective analysis of patients treated at a US centre. Drug
Saf 34(2):117–123. https​://doi.org/10.2165/11585​960-00000​
0000-00000​
69. Dunn N, Juto A, Ryner M, Manouchehrinia A, Piccoli L, Fink K,
Piehl F, Fogdell-Hahn A (2018) Rituximab in multiple sclerosis:
frequency and clinical relevance of anti-drug antibodies. Mult
Scler 24(9):1224–1233. https​://doi.org/10.1177/13524​58517​
72004​4
70. Hu Y, Nie H, Yu HH, Qin C, Wu LJ, Tang ZP, Tian DS (2019)
Efficacy and safety of rituximab for relapsing-remitting multiple
sclerosis: a systematic review and meta-analysis. Autoimmun
Rev 18(5):542–548. https:​ //doi.org/10.1016/j.autrev​ .2019.03.011
71. Salvarani C, Brown RD Jr, Muratore F, Christianson TJH, Galli
E, Pipitone N, Cassone G, Huston J III, Giannini C, Warrington
K, Hunder GG (2019) Rituximab therapy for primary central
nervous system vasculitis: a 6 patient experience and review
of the literature. Autoimmun Rev 18(4):399–405. https​://doi.
org/10.1016/j.autre​v.2018.12.002
72. Alvarez KNIS E, Sillau S, Vollmer T (2019) Tolerability and
safety of switching from rituximab to ocrelizumab: evaluating
factors associated with infusion related reactions—Abstract:
P1402. ECTRIMS Online Library. Alvarez E. 09/13/19; 278602
73. Joerger M (2012) Prevention and handling of acute allergic and
infusion reactions in oncology. Ann Oncol 23(Suppl 10):x313-
319. https​://doi.org/10.1093/annon​c/mds31​4
74. Heusele M, Clerson P, Guery B, Lambert M, Launay D, Lefevre
G, Morell-Dubois S, Maillard H, Le Gouellec N, Hatron PY,
Hachulla E (2014) Risk factors for severe bacterial infections in
13
Journal of Neurology (2022) 269:159–183
patients with systemic autoimmune diseases receiving rituximab.
Clin Rheumatol 33(6):799–805. https​://doi.org/10.1007/s1006​
7-014-2509-2
75. Gottenberg JE, Ravaud P, Bardin T, Cacoub P, Cantagrel A,
Combe B, Dougados M, Flipo RM, Godeau B, Guillevin L, Le
Loet X, Hachulla E, Schaeverbeke T, Sibilia J, Baron G, Mari-
ette X, AutoImmunity and Rituximab registry and French Soci-
ety of Rheumatology (2010) Risk factors for severe infections
in patients with rheumatoid arthritis treated with rituximab in
the autoimmunity and rituximab registry. Arthritis Rheum
62(9):2625–2632. https​://doi.org/10.1002/art.27555​
76. Gea-Banacloche JC (2010) Rituximab-associated infections.
Semin Hematol 47(2):187–198. https​://doi.org/10.1053/j.semin​
hemat​ol.2010.01.002
77. Luna G, Alping P, Burman J, Fink K, Fogdell-Hahn A, Gun-
narsson M, Hillert J, Langer-Gould A, Lycke J, Nilsson P, Salzer
J, Svenningsson A, Vrethem M, Olsson T, Piehl F, Frisell T
(2019) Infection risks among patients with multiple sclerosis
treated with fingolimod, natalizumab, rituximab, and injectable
therapies. JAMA Neurol. https​://doi.org/10.1001/jaman​eurol​
.2019.3365
78. Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven
R, Bathon J, Dougados M, Baldassare A, Ferraccioli G, Chubick
A, Udell J, Cravets MW, Agarwal S, Cooper S, Magrini F (2007)
Safety and efficacy of additional courses of rituximab in patients
with active rheumatoid arthritis: an open-label extension analy-
sis. Arthritis Rheum 56(12):3896–3908. https:​ //doi.org/10.1002/
art.23059​
79. Salzer J, Lycke J, Wickstrom R, Naver H, Piehl F, Svenningsson
A (2016) Rituximab in paediatric onset multiple sclerosis: a case
series. J Neurol 263(2):322–326. https​://doi.org/10.1007/s0041​
5-015-7979-x
80. Durozard P, Maarouf A, Boutiere C, Ruet A, Brochet B, Vuku-
sic S, Carra-Dalliere C, Labauge P, Mathey G, Debouverie M,
Papeix C, Maillart E, Lubetzki C, Bensa C, Gout O, Giannesini
C, Stankoff B, Ciron J, Brassat D, Pelletier J, Rico Lamy A,
Audoin B (2019) Efficacy of rituximab in refractory RRMS. Mult
Scler 25(6):828–836. https​://doi.org/10.1177/13524​58518​77274​
8
81. de Flon P, Gunnarsson M, Laurell K, Soderstrom L, Birgander R,
Lindqvist T, Krauss W, Dring A, Bergman J, Sundstrom P, Sven-
ningsson A (2016) Reduced inflammation in relapsing-remitting
multiple sclerosis after therapy switch to rituximab. Neurology
87(2):141–147. https:​ //doi.org/10.1212/WNL.000000​ 00000​ 0283​
2
82. Rommer PS, Dorner T, Freivogel K, Haas J, Kieseier BC, Kump-
fel T, Paul F, Proft F, Schulze-Koops H, Schmidt E, Wiendl
H, Ziemann U, Zettl UK, GRAID Investigators (2016) Safety
and clinical outcomes of rituximab treatment in patients with
multiple sclerosis and neuromyelitis optica: experience from a
National Online Registry (GRAID). J Neuroimmune Pharmacol
11(1):1–8. https​://doi.org/10.1007/s1148​1-015-9646-5
83. Alldredge B, Jordan A, Imitola J, Racke MK (2018) Safety
and efficacy of rituximab: experience of a single multiple scle-
rosis center. Clin Neuropharmacol 41(2):56–59. https​://doi.
org/10.1097/WNF.00000​00000​00026​8
84. Tony HP, Burmester G, Schulze-Koops H, Grunke M, Henes J,
Kotter I, Haas J, Unger L, Lovric S, Haubitz M, Fischer-Betz
R, Chehab G, Rubbert-Roth A, Specker C, Weinerth J, Holle J,
Muller-Ladner U, Konig R, Fiehn C, Burgwinkel P, Budde K,
Sorensen H, Meurer M, Aringer M, Kieseier B, Erfurt-Berge C,
Sticherling M, Veelken R, Ziemann U, Strutz F, von Wussow P,
Meier FM, Hunzelmann N, Schmidt E, Bergner R, Schwarting
A, Eming R, Hertl M, Stadler R, Schwarz-Eywill M, Wassen-
berg S, Fleck M, Metzler C, Zettl U, Westphal J, Heitmann S,
Herzog AL, Wiendl H, Jakob W, Schmidt E, Freivogel K, Dorner
Journal of Neurology (2022) 269:159–183 179
T, GRAID Investigators (2011) Safety and clinical outcomes of
rituximab therapy in patients with different autoimmune dis-
eases: experience from a national registry (GRAID). Arthritis
Res Ther 13(3):R75. https​://doi.org/10.1186/ar333​7
85. Hellgren J, Risedal A, Kallen K (2020) Rituximab in mul-
tiple sclerosis at general hospital level. Acta Neurol Scand
141(6):491–499. https​://doi.org/10.1111/ane.13225​
86. Mok CC (2013) Rituximab for the treatment of rheumatoid
arthritis: an update. Drug Des Devel Ther 8:87–100. https​://doi.
org/10.2147/DDDT.S4164​5
87. Pyrpasopoulou A, Douma S, Vassiliadis T, Chatzimichailidou
S, Triantafyllou A, Aslanidis S (2011) Reactivation of chronic
hepatitis B virus infection following rituximab administration for
rheumatoid arthritis. Rheumatol Int 31(3):403–404. https​://doi.
org/10.1007/s0029​6-009-1202-2
88. Chen KL, Chen J, Rao HL, Guo Y, Huang HQ, Zhang L, Shao
JY, Lin TY, Jiang WQ, Zou DH, Hu LY, Wirian ML, Cai QQ
(2015) Hepatitis B virus reactivation and hepatitis in diffuse large
B-cell lymphoma patients with resolved hepatitis B receiving
rituximab-containing chemotherapy: risk factors and survival.
Chin J Cancer 34(5):225–234. https​://doi.org/10.1186/s4088​
0-015-0015-9
89. Seto WK, Chan TS, Hwang YY, Wong DK, Fung J, Liu KS, Gill
H, Lam YF, Lie AK, Lai CL, Kwong YL, Yuen MF (2014) Hepa-
titis B reactivation in patients with previous hepatitis B virus
exposure undergoing rituximab-containing chemotherapy for
lymphoma: a prospective study. J Clin Oncol 32(33):3736–3743.
https​://doi.org/10.1200/JCO.2014.56.7081
90. Di Bisceglie AM, Lok AS, Martin P, Terrault N, Perrillo RP,
Hoofnagle JH (2015) Recent US Food and Drug Administration
warnings on hepatitis B reactivation with immune-suppressing
and anticancer drugs: just the tip of the iceberg? Hepatology
61(2):703–711. https​://doi.org/10.1002/hep.27609​
91. (FDA) FaDA (2020) FDA Drug safety communication: boxed
warning and new recommendations to decrease risk of hepati-
tis B reactivation with the immune-suppressing and anti-cancer
drugs Arzerra (ofatumumab) and Rituxan (rituximab). https​://
www.fda.gov/drugs​/drug-safet​y-and-avail​abili​ty/fda-drug-safet​
y-commu​nicat​ion-boxed​-warni​ng-and-new-recom​menda​tions​
-decre​ase-risk-hepat​itis-b. Accessed Nov 2020
92. Goldberg SL, Pecora AL, Alter RS, Kroll MS, Rowley SD,
Waintraub SE, Imrit K, Preti RA (2002) Unusual viral infec-
tions (progressive multifocal leukoencephalopathy and cytomeg-
alovirus disease) after high-dose chemotherapy with autologous
blood stem cell rescue and peritransplantation rituximab. Blood
99(4):1486–1488. https​://doi.org/10.1182/blood​.v99.4.1486
93. Ennishi D, Terui Y, Yokoyama M, Mishima Y, Takahashi S,
Takeuchi K, Ikeda K, Tanimoto M, Hatake K (2008) Increased
incidence of interstitial pneumonia by CHOP combined with
rituximab. Int J Hematol 87(4):393–397. https:​ //doi.org/10.1007/
s1218​5-008-0066-7
94. Sikkema T, Schuiling WJ, Hoogendoorn M (2013) Progressive
multifocal leukoencephalopathy during treatment with rituximab
and CHOP chemotherapy in a patient with a diffuse large B-cell
lymphoma. BMJ Case Rep. https​://doi.org/10.1136/bcr-2012-
00814​2
95. Oshima Y, Tanimoto T, Yuji K, Tojo A (2019) Drug-associ-
ated progressive multifocal leukoencephalopathy in multiple
sclerosis patients. Mult Scler 25(8):1141–1149. https​://doi.
org/10.1177/13524​58518​78607​5
96. Narula S, LaRosa DF, Kamoun M, Dalmau J, Levinson AI (2007)
Progressive multifocal leukoencephalopathy in a patient with
common variable immunodeficiency and abnormal CD8+ T-cell
subset distribution. Ann Allergy Asthma Immunol 98(5):483–
489. https​://doi.org/10.1016/S1081​-1206(10)60764​-8
97. Stasi R, Del Poeta G, Stipa E, Evangelista ML, Trawinska
MM, Cooper N, Amadori S (2007) Response to B-cell deplet-
ing therapy with rituximab reverts the abnormalities of T-cell
subsets in patients with idiopathic thrombocytopenic purpura.
Blood 110(8):2924–2930. https​://doi.org/10.1182/blood​-2007-
02-06899​9
98. Iacobaeus E, Burkill S, Bahmanyar S, Hakim R, Bystrom C,
Fored M, Olsson T, Brundin L, Montgomery S (2018) The
national incidence of PML in Sweden, 1988–2013. Neurology
90(6):e498–e506. https​://doi.org/10.1212/WNL.00000​00000​
00492​6
99. Classifying PML risk with disease modifying therapies—Form-
Sus. (2020). http://forms​us.datas​us.gov.br/novoi​mgarq​/58543​
/13614​899_31236​4.pdf
100. Prosperini L, Scarpazza C, Imberti L, Cordioli C, De Rossi N,
Capra R (2017) Age as a risk factor for early onset of natal-
izumab-related progressive multifocal leukoencephalopathy.
J Neurovirol 23(5):742–749. https​: //doi.org/10.1007/s1336​
5-017-0561-9
101. Kartau M, Sipila JO, Auvinen E, Palomaki M, Verkkoniemi-
Ahola A (2019) Progressive Multifocal Leukoencephalopathy:
current Insights. Degener Neurol Neuromuscul Dis 9:109–121.
https​://doi.org/10.2147/DNND.S2034​05
102. Kridin K, Ahmed AR (2020) Post-rituximab immunoglobulin M
(IgM) hypogammaglobulinemia. Autoimmun Rev 19(3):102466.
https​://doi.org/10.1016/j.autre​v.2020.10246​6
103. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL,
Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Val-
mori D, Romero P, Werner-Favre C, Zubler RH, Browning JL,
Tschopp J (1999) BAFF, a novel ligand of the tumor necrosis fac-
tor family, stimulates B cell growth. J Exp Med 189(11):1747–
1756. https​://doi.org/10.1084/jem.189.11.1747
104. Ireland S, Monson N (2011) Potential impact of B cells on T cell
function in multiple sclerosis. Mult Scler Int 2011:423971. https​
://doi.org/10.1155/2011/42397​1
105. Marcinno A, Marnetto F, Valentino P, Martire S, Balbo A, Drago
A, Leto M, Capobianco M, Panzica G, Bertolotto A (2018)
Rituximab-induced hypogammaglobulinemia in patients with
neuromyelitis optica spectrum disorders. Neurol Neuroimmu-
nol Neuroinflamm 5(6):e498. https:​ //doi.org/10.1212/NXI.00000​
00000​00049​8
106. Etemadifar M, Salari M, Mirmosayyeb O, Serati M, Nikkhah R,
Askari M, Fayyazi E (2017) Efficacy and safety of rituximab in
neuromyelitis optica: review of evidence. J Res Med Sci 22:18.
https​://doi.org/10.4103/1735-1995.20027​5
107. Boleto G, Avouac J, Wipff J, Forien M, Dougados M, Roux C,
Kahan A, Dieude P, Allanore Y (2018) Predictors of hypogam-
maglobulinemia during rituximab maintenance therapy in rheu-
matoid arthritis: a 12-year longitudinal multi-center study. Semin
Arthritis Rheum 48(2):149–154. https​://doi.org/10.1016/j.semar​
thrit​.2018.02.010
108. Isvy A, Meunier M, Gobeaux-Chenevier C, Maury E, Wipff J,
Job-Deslandre C, Kahan A, Allanore Y (2012) Safety of rituxi-
mab in rheumatoid arthritis: a long-term prospective single-
center study of gammaglobulin concentrations and infections.
Joint Bone Spine 79(4):365–369. https​://doi.org/10.1016/j.jbspi​
n.2011.12.004
109. Barmettler S, Ong MS, Farmer JR, Choi H, Walter J (2018) Asso-
ciation of immunoglobulin levels, infectious risk, and mortal-
ity with rituximab and hypogammaglobulinemia. JAMA Netw
Open 1(7):e184169. https​://doi.org/10.1001/jaman​etwor​kopen​
.2018.4169
110. Rozman S, Sonc M, Novakovic BJ (2012) Late-onset neu-
tropenia following primary treatment of diffuse large
B-cell lymphoma with rituximab-containing therapy. Leuk
13

180
Lymphoma 53(10):1945–1948. https​://doi.org/10.3109/10428​
194.2012.67926​6
111. Tesfa D, Palmblad J (2011) Late-onset neutropenia following
rituximab therapy: incidence, clinical features and possible
mechanisms. Expert Rev Hematol 4(6):619–625. https​://doi.
org/10.1586/EHM.11.62
112. Rigal J, Ciron J, Lepine Z, Biotti D (2020) Late-onset neutro-
penia after RITUXIMAB therapy for multiple sclerosis, neuro-
myelitis optica spectrum disorders and MOG-antibody-associ-
ated diseases. Mult Scler Relat Disord 41:102019. https​://doi.
org/10.1016/j.msard​.2020.10201​9
113. Alcala C, Gascon F, Perez-Miralles F, Gil-Perotin S, Navarre
A, Bosca I, Coret F, Casanova B (2018) Efficacy and safety
of rituximab in relapsing and progressive multiple sclerosis: a
hospital-based study. J Neurol 265(7):1690–1697. https​://doi.
org/10.1007/s0041​5-018-8899-3
114. Yamout BI, El-Ayoubi NK, Nicolas J, El Kouzi Y, Khoury SJ,
Zeineddine MM (2018) Safety and efficacy of rituximab in mul-
tiple sclerosis: a retrospective observational study. J Immunol
Res 2018:9084759. https​://doi.org/10.1155/2018/90847​59
115. Wadstrom H, Frisell T, Askling J, Anti-Rheumatic Therapy in
Sweden (ARTIS) Study Group (2017) Malignant neoplasms in
patients with rheumatoid arthritis treated with tumor necrosis
factor inhibitors, tocilizumab, abatacept, or rituximab in clinical
practice: a nationwide cohort study from Sweden. JAMA Intern
Med 177(11):1605–1612. https​://doi.org/10.1001/jamai​ntern​
med.2017.4332
116. Alping P, Askling J, Burman J, Fink K, Fogdell-Hahn A, Gun-
narsson M, Hillert J, Langer-Gould A, Lycke J, Nilsson P, Salzer
J, Svenningsson A, Vrethem M, Olsson T, Piehl F, Frisell T
(2020) Cancer risk for fingolimod, natalizumab, and rituximab
in multiple sclerosis patients. Ann Neurol 87(5):688–699. https​
://doi.org/10.1002/ana.25701​
117. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman
GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK,
Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D,
Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB,
Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA,
Peikert T, Stegeman C, Ytterberg SR, Specks U, RAVE-ITN
Research Group (2010) Rituximab versus cyclophosphamide
for ANCA-associated vasculitis. N Engl J Med 363(3):221–232.
https​://doi.org/10.1056/NEJMo​a0909​905
118. Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP,
Levesque MC, Barohn RJ, Feldman BM, Harris-Love MO,
Koontz DC, Fertig N, Kelley SS, Pryber SL, Miller FW, Rock-
ette HE, RIM Study Group (2013) Rituximab in the treatment
of refractory adult and juvenile dermatomyositis and adult poly-
myositis: a randomized, placebo-phase trial. Arthritis Rheum
65(2):314–324. https​://doi.org/10.1002/art.37754​
119. Fervenza FC, Appel GB, Barbour SJ, Rovin BH, Lafayette RA,
Aslam N, Jefferson JA, Gipson PE, Rizk DV, Sedor JR, Simon JF,
McCarthy ET, Brenchley P, Sethi S, Avila-Casado C, Beanlands
H, Lieske JC, Philibert D, Li T, Thomas LF, Green DF, Jun-
cos LA, Beara-Lasic L, Blumenthal SS, Sussman AN, Erickson
SB, Hladunewich M, Canetta PA, Hebert LA, Leung N, Rad-
hakrishnan J, Reich HN, Parikh SV, Gipson DS, Lee DK, da
Costa BR, Juni P, Cattran DC, Investigators M (2019) Rituximab
or cyclosporine in the treatment of membranous nephropathy. N
Engl J Med 381(1):36–46. https:​ //doi.org/10.1056/NEJMoa​ 1814​
427
120. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh
CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh
D, Walsh M, Westman K, Jayne DR, European Vasculitis Study
Group (2010) Rituximab versus cyclophosphamide in ANCA-
associated renal vasculitis. N Engl J Med 363(3):211–220. https​
://doi.org/10.1056/NEJMo​a0909​169
13
Journal of Neurology (2022) 269:159–183
121. Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley
EA, Bahn RS (2015) Randomized controlled trial of rituximab
in patients with Graves’ orbitopathy. J Clin Endocrinol Metab
100(2):432–441. https​://doi.org/10.1210/jc.2014-2572
122. Diaz-Manera J, Martinez-Hernandez E, Querol L, Klooster R,
Rojas-Garcia R, Suarez-Calvet X, Munoz-Blanco JL, Mazia
C, Straasheijm KR, Gallardo E, Juarez C, Verschuuren JJ, Illa
I (2012) Long-lasting treatment effect of rituximab in MuSK
myasthenia. Neurology 78(3):189–193. https​://doi.org/10.1212/
WNL.0b013​e3182​40798​2
123. Owczarczyk K, Hellmann M, Fliedner G, Rohrs T, Maizus K,
Passon D, Hallek M, Rubbert A (2008) Clinical outcome and
B cell depletion in patients with rheumatoid arthritis receiving
rituximab monotherapy in comparison with patients receiving
concomitant methotrexate. Ann Rheum Dis 67(11):1648–1649.
https​://doi.org/10.1136/ard.2007.08702​3
124. Mease PJ, Cohen S, Gaylis NB, Chubick A, Kaell AT, Greenwald
M, Agarwal S, Yin M, Kelman A (2010) Efficacy and safety of
retreatment in patients with rheumatoid arthritis with previous
inadequate response to tumor necrosis factor inhibitors: results
from the SUNRISE trial. J Rheumatol 37(5):917–927. https​://
doi.org/10.3899/jrheu​m.09044​2
125. Kaegi C, Wuest B, Schreiner J, Steiner UC, Vultaggio A, Matucci
A, Crowley C, Boyman O (2019) Systematic review of safety
and efficacy of rituximab in treating immune-mediated disor-
ders. Front Immunol 10:1990. https​://doi.org/10.3389/fimmu​
.2019.01990​
126. Kimby E (2005) Tolerability and safety of rituximab (MabThera).
Cancer Treat Rev 31(6):456–473. https​://doi.org/10.1016/j.
ctrv.2005.05.007
127. Yri OE, Torfoss D, Hungnes O, Tierens A, Waalen K, Nordoy
T, Dudman S, Kilander A, Wader KF, Ostenstad B, Ekanger
R, Meyer P, Kolstad A (2011) Rituximab blocks protective
serologic response to influenza A (H1N1) 2009 vaccination in
lymphoma patients during or within 6 months after treatment.
Blood 118(26):6769–6771. https​://doi.org/10.1182/blood​-2011-
08-37264​9
128. Nazi I, Kelton JG, Larche M, Snider DP, Heddle NM, Crowther
MA, Cook RJ, Tinmouth AT, Mangel J, Arnold DM (2013)
The effect of rituximab on vaccine responses in patients with
immune thrombocytopenia. Blood 122(11):1946–1953. https​://
doi.org/10.1182/blood​-2013-04-49409​6
129. Cho A, Bradley B, Kauffman R, Priyamvada L, Kovalenkov
Y, Feldman R, Wrammert J (2017) Robust memory responses
against influenza vaccination in pemphigus patients previously
treated with rituximab. JCI Insight 2(12):e93222. https​://doi.
org/10.1172/jci.insig​ht.93222​
130. Hoyer BF, Manz RA, Radbruch A, Hiepe F (2005) Long-lived
plasma cells and their contribution to autoimmunity. Ann N Y
Acad Sci 1050:124–133. https:​ //doi.org/10.1196/annals​ .1313.014
131. Sutter JA, Kwan-Morley J, Dunham J, Du YZ, Kamoun M,
Albert D, Eisenberg RA, Luning Prak ET (2008) A longitudinal
analysis of SLE patients treated with rituximab (anti-CD20):
factors associated with B lymphocyte recovery. Clin Immunol
126(3):282–290. https​://doi.org/10.1016/j.clim.2007.11.012
132. Zrzavy T, Kollaritsch H, Rommer PS, Boxberger N, Loebermann
M, Wimmer I, Winkelmann A, Zettl UK (2019) Vaccination in
multiple sclerosis: friend or foe? Front Immunol 10:1883. https​
://doi.org/10.3389/fimmu​.2019.01883​
133. (MabThera) EAoM-I-R (2020) https​://www.ema.europ​a.eu/en/
docum​ents/produ​ct-infor ​matio​n/mabth​era-epar-produ​ct-infor​
matio​n_en.pdf
134. Administration FaD (2020) https​://www.acces​sdata​.fda.gov/
drugs​atfda​_docs/label​/2012/10370​5s536​7s538​8lbl.pdf
135. Gelfand JM, Cree BAC, Hauser SL (2017) Ocrelizumab and
other CD20(+) B-cell-depleting therapies in multiple sclerosis.
Journal of Neurology (2022) 269:159–183 181
Neurotherapeutics 14(4):835–841. https:​ //doi.org/10.1007/s1331​
1-017-0557-4
136. JR (2019) Rituximab for treatment of aggressive multiple scle-
rosis during pregnancy: a case study. Academy of American
Neurology Annual Meeting, May 4–10, 2019; Philadelphia, PA
Abstract P42–103
137. LaHue S KK, Rutatangwa A, et al (2019) Minimal concentrations
of rituximab in the breastmilk of women treated for multiple
sclerosis. Academy of American Neurology Annual Meeting,
May 4–10, 2019; Philadelphia, PA Abstract P42–097
138. Matias-Guiu J, Gomez-Pinedo U, Montero-Escribano P, Gomez-
Iglesias P, Porta-Etessam J, Matias-Guiu JA (2020) Should
we expect neurological symptoms in the SARS-CoV-2 epi-
demic? Neurologia 35(3):170–175. https​://doi.org/10.1016/j.
nrl.2020.03.001
139. Salama S, Ahmed SF, Ibrahim Ismail I, Alroughani R (2020)
Impact of coronavirus disease (COVID-19) pandemic on mul-
tiple sclerosis care. Clin Neurol Neurosurg 197:106203. https​://
doi.org/10.1016/j.cline​uro.2020.10620​3
140. Sokolowska M, Lukasik Z, Agache I, Akdis CA, Akdis D, Akdis
M, Barcik W, Brough H, Eiwegger T, Eliaszewicz A, Eyerich
S, Feleszko W, Gomez Casado C, Hoffmann-Sommergruber K,
Janda J, Jimenez-Saiz R, Jutel M, Knol E, Kortekaas Krohn I,
Kothari A, Makowska J, Moniuszko M, Morita H, O’Mahony L,
Nadeau K, Ozdemir C, Pali-Scholl I, Palomares O, Papaleo F,
Prunicki M, Schmidt-Weber CB, Sediva A, Schwarze J, Shamji
MH, Tramper-Stranders G, van de Veen W, Untersmayr E (2020)
Immunology of COVID-19: mechanisms, clinical outcome, diag-
nostics and perspectives—a report of the European Academy of
Allergy and Clinical Immunology (EAACI). Allergy. https:​ //doi.
org/10.1111/all.14462​
141. Novi G, Mikulska M, Briano F, Toscanini F, Tazza F, Uccelli A,
Inglese M (2020) COVID-19 in a MS patient treated with ocre-
lizumab: does immunosuppression have a protective role? Mult
Scler Relat Disord 42:102120. https​://doi.org/10.1016/j.msard​
.2020.10212​0
142. Tay MZ, Poh CM, Renia L, MacAry PA, Ng LFP (2020) The
trinity of COVID-19: immunity, inflammation and intervention.
Nat Rev Immunol 20(6):363–374. https​://doi.org/10.1038/s4157​
7-020-0311-8
143. Safavi F, Nourbakhsh B, Azimi AR (2020) B-cell depleting thera-
pies may affect susceptibility to acute respiratory illness among
patients with multiple sclerosis during the early COVID-19 epi-
demic in Iran. Mult Scler Relat Disord 43:102195. https​://doi.
org/10.1016/j.msard​.2020.10219​5
144. Maria Pia Sormani NDR, Irene Schiavetti Luca, Carmisciano
CC, Lucia Moiola, Marta Radaelli, Paolo, Immovilli Marco
Capobianco MT, Paola Zaratin, Gioacchino Tedeschi GC, Mario
Alberto Battaglia, Francesco Patti MS, and the Musc-19 study
group (2020) Disease modifying therapies and COVID-19 sever-
ity in multiple sclerosis. Lancet Neurol. Available at SSRN: https​
://doi.org/10.2139/ssrn.36312​44
145. Coles ALM, Giovannoni G, Anderson P, Dorsey-Campbell R,
Qualie M, Vieira JJ (2020) ABN guidance on the use of disease-
modifying therapies in multiple sclerosis in response to the threat
of a coronavirus epidemic. https​://cdn.ymaws​.com/www.theab​
n.org/resour​ ce/collec​ tion/​ 65C334​ C7-30FA-45DB-93AA-74B3A​
3A202​93/02.04.20_ABN_Guida​nce_on_DMTs_for_MS_and_
COVID​19_VERSI​ON_4_April​_2nd.pdf. Accessed Nov 2020
146. Tepasse PR, Hafezi W, Lutz M, Kuhn J, Wilms C, Wiewrodt R,
Sackarnd J, Keller M, Schmidt HH, Vollenberg R (2020) Persist-
ing SARS-CoV-2 viraemia after rituximab therapy: two cases
with fatal outcome and a review of the literature. Br J Haematol
190(2):185–188. https​://doi.org/10.1111/bjh.16896​
147. Wurm H, Attfield K, Iversen AK, Gold R, Fugger L, Haghikia A
(2020) Recovery from COVID-19 in a B-cell-depleted multiple
sclerosis patient. Mult Scler 26(10):1261–1264. https​://doi.
org/10.1177/13524​58520​94379​1
148. Baker D, Roberts CAK, Pryce G, Kang AS, Marta M, Reyes
S, Schmierer K, Giovannoni G, Amor S (2020) COVID-19
vaccine-readiness for anti-CD20-depleting therapy in autoim-
mune diseases. Clin Exp Immunol 202(2):149–161. https​://doi.
org/10.1111/cei.13495​
149. ClinicalTrials.gov (2020) A study to evaluate the effects of ocre-
lizumab on immune responses in participants with relapsing
forms of multiple sclerosis. Accessed 22 Nov 2020
150. Montero-Escribano P, Matias-Guiu J, Gomez-Iglesias P, Porta-
Etessam J, Pytel V, Matias-Guiu JA (2020) Anti-CD20 and
COVID-19 in multiple sclerosis and related disorders: A case
series of 60 patients from Madrid. Spain Mult Scler Relat Disord
42:102185. https​://doi.org/10.1016/j.msard​.2020.10218​5
151. D’Amico E, Chisari CG, Gitto L, Zanghi A, Toscano S, Patti F
(2019) Pharmacoeconomics of synthetic therapies for multiple
sclerosis. Expert Opin Pharmacother 20(11):1331–1340. https​://
doi.org/10.1080/14656​566.2019.16158​80
152. Du FH, Mills EA, Mao-Draayer Y (2017) Next-generation anti-
CD20 monoclonal antibodies in autoimmune disease treatment.
Auto Immun Highlights 8(1):12. https​://doi.org/10.1007/s1331​
7-017-0100-y
153. Rognoni C, Bertolani A, Jommi C (2018) Budget impact analy-
sis of rituximab biosimilar in Italy from the hospital and payer
perspectives. Glob Reg Health Technol Assess 5(1):1–11. https​
://doi.org/10.1177/22842​40318​78428​
154. Hartung DM (2017) Economics and cost-effectiveness of
multiple sclerosis therapies in the USA. Neurotherapeutics
14(4):1018–1026. https​://doi.org/10.1007/s1331​1-017-0566-3
155. Genenentech (2020) OCREVUS pricing and financial support
https​://www.ocrev​us.com/patie​nt/cost.html Accessed 20 Nov
2020
156. Mullard A (2017) Bracing for the biosimilar wave. Nat Rev Drug
Discov 16(3):152–154. https​://doi.org/10.1038/nrd.2017.36
157. Simoens S (2011) Biosimilar medicines and cost-effectiveness.
Clinicoecon Outcomes Res 3:29–36. https​://doi.org/10.2147/
CEOR.S1249​4
158. Montserrat E (2003) Rituximab in chronic lymphocytic leu-
kemia. Semin Oncol 30(1S2):34–39. https​://doi.org/10.1053/
sonc.2003.50033​
159. Boremalm M, Juto A, Axelsson M, Novakova L, Frisell T,
Svenningsson A, Lycke J, Piehl F, Salzer J (2019) Natalizumab,
rituximab and fingolimod as escalation therapy in multiple scle-
rosis. Eur J Neurol 26(8):1060–1067. https​://doi.org/10.1111/
ene.13936​
160. Roll P, Palanichamy A, Kneitz C, Dorner T, Tony HP (2006)
Regeneration of B cell subsets after transient B cell depletion
using anti-CD20 antibodies in rheumatoid arthritis. Arthritis
Rheum 54(8):2377–2386. https​://doi.org/10.1002/art.22019​
161. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi
D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN,
Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW,
Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley
RL, Sartor O, Green D, Major EO, Bennett CL (2009) Progres-
sive multifocal leukoencephalopathy after rituximab therapy in
HIV-negative patients: a report of 57 cases from the Research on
Adverse Drug Events and Reports project. Blood 113(20):4834–
4840. https​://doi.org/10.1182/blood​-2008-10-18699​9
162. Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson
M, Parks D, Perry A, Yerra R, Schmidt R, Alvarez E, Tyler KL
(2011) Rituximab-associated progressive multifocal leukoen-
cephalopathy in rheumatoid arthritis. Arch Neurol 68(9):1156–
1164. https​://doi.org/10.1001/archn​eurol​.2011.103
163. Nielsen AS, Miravalle A, Langer-Gould A, Cooper J, Edwards
KR, Kinkel RP (2012) Maximally tolerated versus minimally
13

182
effective dose: the case of rituximab in multiple sclerosis. Mult
Scler 18(3):377–378. https​://doi.org/10.1177/13524​58511​41863​
1 randomised, double-blind trial to demonstrate bioequivalence
164. Shirani A, Okuda DT, Stuve O (2016) Therapeutic advances
and future prospects in progressive forms of multiple sclerosis.
Neurotherapeutics 13(1):58–69. https​://doi.org/10.1007/s1331​
1-015-0409-z
165. Studer V, Rossi S, Motta C, Buttari F, Centonze D (2014) Periph-
eral B cell depletion and central proinflammatory cytokine reduc-
tion following repeated intrathecal administration of rituximab in
progressive Multiple Sclerosis. J Neuroimmunol 276(1–2):229–
231. https​://doi.org/10.1016/j.jneur​oim.2014.08.617
166. Svenningsson A, Bergman J, Dring A, Vagberg M, Birgander R,
Lindqvist T, Gilthorpe J, Bergenheim T (2015) Rapid depletion
of B lymphocytes by ultra-low-dose rituximab delivered intrathe-
cally. Neurol Neuroimmunol Neuroinflamm 2(2):e79. https:​ //doi.
org/10.1212/NXI.00000​00000​00007​9
167. Ellrichmann G, Bolz J, Peschke M, Duscha A, Hellwig K, Lee
DH, Linker RA, Gold R, Haghikia A (2019) Peripheral CD19(+)
B-cell counts and infusion intervals as a surrogate for long-term
B-cell depleting therapy in multiple sclerosis and neuromyeli-
tis optica/neuromyelitis optica spectrum disorders. J Neurol
266(1):57–67. https​://doi.org/10.1007/s0041​5-018-9092-4
168. Yi JS, Decroos EC, Sanders DB, Weinhold KJ, Guptill JT (2013)
Prolonged B-cell depletion in MuSK myasthenia gravis following
rituximab treatment. Muscle Nerve 48(6):992–993. https​://doi.
org/10.1002/mus.24063​
169. Memon AB, Javed A, Caon C, Srivastawa S, Bao F, Bernit-
sas E, Chorostecki J, Tselis A, Seraji-Bozorgzad N, Khan O
(2018) Long-term safety of rituximab induced peripheral B-cell
depletion in autoimmune neurological diseases. PLoS ONE
13(1):e0190425. https​://doi.org/10.1371/journ​al.pone.01904​25
170. Kim SH, Kim W, Li XF, Jung IJ, Kim HJ (2011) Repeated treat-
ment with rituximab based on the assessment of peripheral cir-
culating memory B cells in patients with relapsing neuromyelitis
optica over 2 years. Arch Neurol 68(11):1412–1420. https​://doi.
org/10.1001/archn​eurol​.2011.154
171. Jurczak W, Dlugosz-Danecka M (2020) Rituximab biosimilars
in clinical practice. Leuk Lymphoma 61(7):1523–1524. https​://
doi.org/10.1080/10428​194.2020.17880​16
172. Initiative GaB (2020) EMA approval for rituximab biosimilar
Truxima
173. (EMA) EMA (2020) Rixathon https​://www.ema.europ​a.eu/en/
medic​ines/human​/EPAR/rixat​hon. Accessed 10 Nov 2020
174. Yoo DH, Suh CH, Shim SC, Jeka S, Cons-Molina FF, Hrycaj
P, Wiland P, Lee EY, Medina-Rodriguez FG, Shesternya P,
Radominski S, Stanislav M, Kovalenko V, Sheen DH, Myasou-
tova L, Lim MJ, Choe JY, Lee SJ, Lee SY, Kwon TS, Park W
(2017) A multicentre randomised controlled trial to compare the
pharmacokinetics, efficacy and safety of CT-P10 and innova-
tor rituximab in patients with rheumatoid arthritis. Ann Rheum
Dis 76(3):566–570. https​://doi.org/10.1136/annrh​eumdi​s-2016-
20954​0
175. Visser J, Feuerstein I, Stangler T, Schmiederer T, Fritsch C,
Schiestl M (2013) Physicochemical and functional comparability
between the proposed biosimilar rituximab GP2013 and origina-
tor rituximab. BioDrugs 27(5):495–507. https:​ //doi.org/10.1007/
s4025​9-013-0036-3
176. Jurczak W, Moreira I, Kanakasetty GB, Munhoz E, Echeveste
MA, Giri P, Castro N, Pereira J, Akria L, Alexeev S, Osmanov E,
Zhu P, Alexandrova S, Zubel A, Harlin O, Amersdorffer J (2017)
Rituximab biosimilar and reference rituximab in patients with
previously untreated advanced follicular lymphoma (ASSIST-
FL): primary results from a confirmatory phase 3, double-blind,
randomised, controlled study. Lancet Haematol 4(8):e350–e361.
https​://doi.org/10.1016/S2352​-3026(17)30106​-0
13
Journal of Neurology (2022) 269:159–183
177. Smolen JS, Cohen SB, Tony HP, Scheinberg M, Kivitz A, Bal-
anescu A, Gomez-Reino J, Cen L, Zhu P, Shisha T (2017) A
of GP2013 and reference rituximab combined with methotrex-
ate in patients with active rheumatoid arthritis. Ann Rheum Dis
76(9):1598–1602. https​://doi.org/10.1136/annrh​eumdi​s-2017-
21128​1
178. Perez T, Rico A, Boutiere C, Maarouf A, Roudot M, Honore
S, Pelletier J, Bertault-Peres P, Audoin B (2020) Compari-
son of rituximab originator (MabThera((R))) to biosimilar
(Truxima((R))) in patients with multiple sclerosis. Mult Scler.
https​://doi.org/10.1177/13524​58520​91217​0
179. Whittam DH, Tallantyre EC, Jolles S, Huda S, Moots RJ, Kim
HJ, Robertson NP, Cree BAC, Jacob A (2019) Rituximab in neu-
rological disease: principles, evidence and practice. Pract Neurol
19(1):5–20. https​://doi.org/10.1136/pract​neuro​l-2018-00189​9
180. Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C,
Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernan-
dez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents
A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J
(2013) Treatment and prognostic factors for long-term outcome
in patients with anti-NMDA receptor encephalitis: an observa-
tional cohort study. Lancet Neurol 12(2):157–165. https​://doi.
org/10.1016/S1474​-4422(12)70310​-1
181. Benedetti L, Briani C, Franciotta D, Fazio R, Paolasso I, Comi
C, Luigetti M, Sabatelli M, Giannini F, Mancardi GL, Schenone
A, Nobile-Orazio E, Cocito D (2011) Rituximab in patients
with chronic inflammatory demyelinating polyradiculoneuropa-
thy: a report of 13 cases and review of the literature. J Neurol
Neurosurg Psychiatry 82(3):306–308. https​://doi.org/10.1136/
jnnp.2009.18891​2
182. Salvarani C, Brown RD Jr, Huston J 3rd, Morris JM, Hunder GG
(2014) Treatment of primary CNS vasculitis with rituximab: case
report. Neurology 82(14):1287–1288. https​://doi.org/10.1212/
WNL.00000​00000​00029​3
183. Damato V, Evoli A, Iorio R (2016) Efficacy and safety of rituxi-
mab therapy in neuromyelitis optica spectrum disorders: a sys-
tematic review and meta-analysis. JAMA Neurol 73(11):1342–
1348. https​://doi.org/10.1001/jaman​eurol​.2016.1637
184. Palace J, Leite MI, Jacob A (2012) A practical guide to the treat-
ment of neuromyelitis optica. Pract Neurol 12(4):209–214. https​
://doi.org/10.1136/pract​neuro​l-2012-00023​7
185. Yang CS, Yang L, Li T, Zhang DQ, Jin WN, Li MS, Su N, Zhang-
ning N, Liu Q, Shao ZH, Yu C, Shi FD (2013) Responsiveness to
reduced dosage of rituximab in Chinese patients with neuromy-
elitis optica. Neurology 81(8):710–713. https​://doi.org/10.1212/
WNL.0b013​e3182​a1aac​7
186. Zhang M, Zhang C, Bai P, Xue H, Wang G (2017) Effective-
ness of low dose of rituximab compared with azathioprine
in Chinese patients with neuromyelitis optica: an over 2-year
follow-up study. Acta Neurol Belg 117(3):695–702. https​://doi.
org/10.1007/s1376​0-017-0795-6
187. Jones RB, Furuta S, Tervaert JW, Hauser T, Luqmani R, Morgan
MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P,
Walsh M, Westman K, Jayne DR, European Vasculitis S (2015)
Rituximab versus cyclophosphamide in ANCA-associated renal
vasculitis: 2-year results of a randomised trial. Ann Rheum Dis
74(6):1178–1182. https​://doi.org/10.1136/annrh​eumdi​s-2014-
20640​4
188. National Institute for Health and Care Excellence technology
appraisal guidance TA308 Rituximab in combination with glu-
cocorticoids for treating anti-neutrophil cytoplasmic antibody-
associated vasculitis. https​://www.nice.org.uk/guida​nce/ta308​/
chapt​er/1-Guida​nce. Accessed 16 Jun 2020
189. Iorio R, Damato V, Alboini PE, Evoli A (2015) Efficacy and
safety of rituximab for myasthenia gravis: a systematic review
Journal of Neurology (2022) 269:159–183 183

and meta-analysis. J Neurol 262(5):1115–1119. https​://doi.
org/10.1007/s0041​5-014-7532-3
190. Tandan R, Hehir MK 2nd, Waheed W, Howard DB (2017) Rituxi-
mab treatment of myasthenia gravis: a systematic review. Muscle
Nerve 56(2):185–196. https​://doi.org/10.1002/mus.25597​
191. Amor S, Baker D, Khoury SJ, Schmierer K, Giovanonni G (2020)
SARS-CoV-2 and multiple sclerosis: not all immune depleting
DMTs are equal or bad. Ann Neurol 87(6):794–797. https​://doi.
org/10.1002/ana.25770​

13